Methods and compositions for detecting autoimmune disorders

ABSTRACT

This invention provides methods and compositions useful for detecting autoimmune disorders.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 13/333,775 filed Dec. 21, 2011, which is a continuation of U.S. patent application Ser. No. 12/749,524 filed Mar. 30, 2010, which is a continuation of U.S. patent application Ser. No. 11/739,606 filed on Apr. 24, 2007, claiming priority under 35 USC 119(e) to U.S. Provisional Application Ser. No. 60/794,393 filed on Apr. 24, 2006, all of which are hereby incorporated herein in their entirety.

TECHNICAL FIELD

The present invention relates generally to the fields of molecular determination of autoimmune diseases. More specifically, the invention concerns methods and compositions based on unique molecular signatures associated with various aspects of autoimmune disorders.

BACKGROUND

A number of autoimmune disorders are now believed to be characterized by the production of autoantibodies against a variety of self antigens. For example, systemic lupus erythematous (SLE) is an autoimmune disease in which autoantibodies cause organ damage by binding to host cells and tissues and by forming immune complexes that deposit in vascular tissues and activate immune cells. Sjogren's syndrome is an autoimmune disease characterized by inflammation in the glands of the body. Other autoimmune disorders are also commonly found, including but not limited to IgA nephropathy, psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, etc.

Interferon alpha (IFN-α) is a Type I interferon strongly implicated in the etiology of a number of immune disorders, such as SLE. It is believed that treatment approaches involving disruption of IFN-α signaling may be an effective treatment for such disorders. IFN-α levels are known to be elevated in SLE, and treatment of patients with IFN-α has been observed to reversibly cause symptoms similar to SLE in recipients. Numerous other lines of evidence have linked IFN-α and SLE.

The mechanisms by which IFN-α exerts its effects on the transcription of genes in target cells has been extensively investigated. The second messenger cascade has been determined, cis-regulatory binding sites for activated transcription factors have been defined, and several studies have explored what genes' expression is modulated. The most comprehensive of these studies have been performed with oligonucleotide microarrays, but definitions of interferon response gene expression profiles are still not complete, at least in part because until recently microarrays have not contained a very complete set of reporters for the genes of the human genome, and also because a variety of technical difficulties prevented identification of broadly applicable yet simple sets of marker genes that reliably correlate with pathological conditions of interest.

One of the most difficult challenges in clinical management of autoimmune diseases is the accurate and early identification of the diseases in a patient. To this end, it would be highly advantageous to have molecular-based diagnostic methods that can be used to objectively identify presence and/or extent of disease in a patient. The invention described herein provides these methods and other benefits.

All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.

DISCLOSURE OF THE INVENTION

The invention provides methods and compositions for identifying autoimmune disorders based at least in part on identification of the gene(s) whose expression is associated with presence and/or extent of systemic lupus erythematosus (SLE), wherein SLE is in turn a prototypical autoimmune disease whose disease-associated gene signatures are also applicable in other autoimmune diseases. For example, as described herein, in one embodiment, genes modulated in response to signaling by IFN-α were identified. Information generated by this approach was then tested and modified to develop a concise and quantitative measure of the degree to which cell or tissue samples exhibit responses characteristic of autoimmune disorders. As shown herein, detection of one or more of specific genes disclosed herein can be a useful and informative indicator of presence and/or extent of autoimmune disorders in a patient. Moreoever, metrics or equivalent quotients that are indicative of interferonassociated disease presentation and/or severity can be generated by appropriate transformation of biomarker gene expression information. Exemplary transformations and resultant metrics are disclosed herein, generated based on gene expression data that are also disclosed herein.

In one aspect, the invention provides a method comprising determining whether a subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein presence of said, cell indicates that the subject has an autoimmune disorder.

In one aspect, the invention provides a method of predicting responsiveness of a subject to autoimmune disease therapy, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein presence of said cell indicates that the subject would be responsive to the autoimmune disease therapy.

In one aspect, the invention provides a method for monitoring minimal residual disease in a subject treated for an autoimmune disease, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of presence of minimal residual autoimmune disease.

In one aspect, the invention provides a method for detecting an autoimmune disease state in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of presence of an autoimmune disease state in the subject.

In one aspect, the invention provides a method for assessing predisposition of a subject to develop an autoimmune disorder, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of a predisposition for the subject to develop the autoimmune disorder.

In one aspect, the invention provides a method for diagnosing an autoimmune disorder in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell indicates that the subject has said autoimmune disorder.

In one aspect, the invention provides a method for distinguishing between active and inactive disease states (e.g., active and inactive SLE) in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell indicates that the subject has the autoimmune disorder in an active state.

In one aspect, the invention provides a method for determining presence and/or elevation of anti-dsDNA antibodies in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell indicates presence and/or elevation of anti-dsDNA antibodies in the subject.

Methods of the invention provide information useful for determining appropriate clinical intervention steps, if and as appropriate. Therefore, in one embodiment of a method of the invention, the method further comprises a clinical intervention step based on results of the assessment of the expression of one or more of the genes listed in Table 1, 2 and/or 3 (including, e.g., any combination of genes (e.g., those listed in Table 4)). For example, appropriate intervention may involve prophylactic and treatment steps, or adjustment(s) of any then-current prophylactic or treatment steps based on gene expression information obtained by a method of the invention.

As would be evident to one skilled in the art, in any method of the invention, while detection of increased expression of a gene would positively indicate a characteristic of a disease (e.g., presence, stage or extent of a disease), non-detection of increased expression of a gene would also be informative by providing the reciprocal characterization of the disease.

In one aspect, the invention provides a composition comprising polynucleotides capable of specifically hybridizing to at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3, or complements of such genes. In one embodiment, the polynucleotides are provided as an array, gene chip, or gene set (e.g., a set of genes or fragments thereof, provided separately or as a mixture).

In one aspect, the invention provides a kit comprising a composition the invention, and instructions for using the composition to detect an autoimmune disorder by determining whether expression of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 are at a level greater than the expression level of the respective genes in a normal reference sample. In one embodiment, the composition of the invention comprises an array/gene chip/gene set capable of specifically hybridizing to at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3. In one embodiment, the composition of the invention comprises nucleic acid molecules encoding at least a portion of a polypeptide encoded by a gene listed in Table 1, 2 and/or 3. In one embodiment, the composition of the invention comprises nucleic acid primers capable of binding to and effecting polymerization (e.g., amplification) of at least a portion of a gene listed in Table 1, 2 and/or 3. In one embodiment, the composition of the invention comprises a binding agent (e.g., primer, probe) that specifically detects a gene (or complement thereof) (or corresponding gene product) listed in Table 1, 2 and/or 3. In one embodiment, the composition of the invention comprises a binding agent that specifically binds to at least a portion of a polypeptide encoded by a gene listed in Table 1, 2 and/or 3.

Methods and compositions of the invention may comprise one or more of the genes listed in Table 1, 2 and/or 3. If more than one gene is utilized or included in a method or composition of the invention, the more than one gene can be any combination of any number of the genes as listed (in no particular order) in Table 1, 2 and/or 3. For example, in one embodiment, a combination of genes comprises only two genes that are listed, namely OAS3 and HERC5. In one embodiment, a combination of genes comprises only three, only four, only five, or only six genes that are listed. In one embodiment, a combination of genes comprises at least two, at least three, at least four, at least five, or at least six genes that are listed. In another embodiment, a combination of genes comprises OAS3, HERC5, and one or more of the other genes listed in Table 1, 2 and/or 3. In one embodiment, a gene combination of the invention comprises, consists, or consists essentially of a 3-gene combination (Genes 1, 2 and 3) as indicated in Table 4B. In one embodiment, such 3-gene combination is indicated as having a Pearson correlation value of at least about 0.7, or at least about 0.75, or at least about 0.8, or at least about 0.85, or at least about 0.9, or at least about 0.95, or at least about 0.97, or at least about 0.98, or at least about 0.99. In one embodiment, such 3-gene combination comprises (1) IFIT4, OAS1, and MX1; or (2) OASL, CHMP5, and ZBP1; or (3) IFI44L, OASL, and CIG5; or (4) IFI44L, CIG5, and ZBP1; or (5) EPSTI1, TYKI, and MX1; or (6) IFIT4, HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, and ZBP1; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OAS1, and IFIT1; or (11) EPSTI1, HERC5, and TYKI; or (12) IFI44L, EPSTI1, and OASL; or (13) IFI44L, EPSTI1, and OAS3; or (14) EPSTI1, TYKI, and IFIT1; or (15) G1P2, SAMD9L, and SP110. In yet another embodiment, a combination of genes comprises one or more of the genes listed in Table 1, 2 and/or 3, further combined with one or more other genes that are not listed in Table 1, 2 and/or 3 (e.g., a gene known to be associated with an autoimmune disease but not associated with induction by interferons specifically).

In any of the embodiments of the invention described herein, one or more reference genes (i.e., genes that, when assessed by themselves, are not known to be indicative of the disease and/or condition of interest) may be included. Such reference genes may include housekeeping genes. For example, suitable reference genes may be housekeeping genes that can serve as reference/control genes indicative of baseline gene expression levels in a sample. Thus, for example, in one embodiment, one or more genes listed in Tables 1, 2, 3 and/or 4 are used in combination with one or more housekeeping genes such as ribosomal protein L19 (RPL19; NP_(—)000972), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), actins (e.g. β-actin), tubulins, hypoxantine phsophoribosyltransferase (HRPT), and other ribosomal proteins/genes (e.g., 28S, 18S).

In one aspect, the invention provides a method of identifying a metric value correlated with presence and/or extent of an autoimmune disorder in a subject or sample, said method comprising:

(a) estimating a group of probesets that is collectively associated with a pattern wherein expression of genes represented by the probesets is associated with a disease characteristic;

(b) generating a weighting factor that weight probesets in accordance with a scale reflecting extent of match of each individual probeset to trend of the group of probesets, and calculating the correlation coefficient of each probeset's profile to the mean profile calculated;

(c) determining a scaling factor, wherein the scaling factor is the value required to scale individual probesets to 1;

(d) multiplying the scaling factor by the weighting factor to generate a composite factor;

(e) multiplying a normal blood sample's signatures with the composite factor, and the averaging the resulting values across both probesets and samples to generate an average value, and inverting the average value to yield a global scaling factor;

(f) multiplying each weighting factor by the global scaling factor to obtain a vector of scalar values, and multiplying the scalar values by an expression signature from a sample of interest, and averaging the resulting values to yield a single metric that is indicative of degree of gene expression associated with Type I interferons in the sample.

In one embodiment of the method of the preceding paragraph, in step (a), the group of probesets comprises probesets that include, or cluster around, the core most-tightly-correlated pair of probesets in subcluster associated with a disease characteristic.

In one embodiment of the method of the preceding paragraphs, in step (b), the factor is generated by transforming expression data of the group of probesets into z-scores comprising mean scaling to 1, base-2 log transformation, then scaling to a standard deviation of the mean of 1.

In one embodiment of the method of the preceding paragraphs, in step (e), the global scaling factor is useful for transforming output of the average of probesets from a sample of interest into a metric, wherein the metric is 1 if the sample is from a normal, healthy subject.

In one embodiment of the method of any of the preceding paragraphs, the group of probesets comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or any number up to all of those listed in Table 1, 2 and/or 3. In one embodiment, the group of probesets comprises all those listed in Table 1, 2 and/or 3.

In one aspect, the invention provides a method comprising comparing a first metric obtained by a method described herein for a sample obtained from a subject of interest to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric indicates presence of an autoimmune disorder in the subject of interest.

In one aspect, the invention provides a method of predicting responsiveness of a subject to autoimmune disease therapy, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric indicates the subject would be responsive to the autoimmune disease therapy.

In one aspect, the invention provides a method for monitoring minimal residual disease in a subject treated for an autoimmune disease, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased and/or untreated) sample, wherein a first metric that is higher than a reference metric is indicative of presence of minimal residual autoimmune disease.

In one aspect, the invention provides a method for detecting an autoimmune disease state, said method comprising comparing a first metric obtained by a method described herein for a sample from a subject suspected of having the autoimmune disease state to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric is indicative of presence of the autoimmune disease state in the subject.

In one aspect, the invention provides a method for assessing predisposition of a subject to develop an autoimmune disorder, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric is indicative of a predisposition for the subject to develop the autoimmune disorder.

In one aspect, the invention provides a method for diagnosing an autoimmune disorder in a subject, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric indicates that the subject has said autoimmune disorder.

In one aspect, the invention provides a method for distinguishing between active and inactive disease states (e.g., active and inactive SLE) in a subject, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, nondiseased) sample, wherein a first metric that is higher than a reference metric indicates that the subject has the autoimmune disorder in an active state.

In one aspect, the invention provides a method for determining presence and/or elevation of anti-dsDNA antibodies in a subject, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric indicates presence and/or elevation of anti-dsDNA antibodies in the subject.

In one embodiment, a reference metric is obtained using a method described herein for a sample from a control sample (e.g., as obtained from a healthy and/or non-diseased and/or untreated tissue, cell and/or subject).

The steps in the methods for examining expression of one or more biomarkers may be conducted in a variety of assay formats, including assays detecting mRNA expression (including but not limited to converting mRNA to cDNA, optionally followed by nucleic acid amplification), enzymatic assays detecting presence of enzymatic activity, and immunohistochemistry assays. Optionally, the tissue or cell sample comprises disease tissue or cells.

Still further methods of the invention include methods of treating a disorder in a mammal, such as an immune related disorder, comprising steps of obtaining tissue or a cell sample from the mammal, examining the tissue or cells for expression (e.g., amount of expression) of one or more biomarkers, and upon determining said tissue or cell sample expresses said one or more biomarkers (e.g., wherein the biomarkers are expressed in amounts greater than a reference (control) sample), administering an effective amount of a therapeutic agent to said mammal. The steps in the methods for examining expression of one or more biomarkers may be conducted in a variety of assay formats, including assays immunohistochemistry assays. Optionally, the methods comprise treating an autoimmune disorder in a mammal. Optionally, the methods comprise administering an effective amount of a targeted therapeutic agent (e.g., an antibody that binds and/or blocks activity of Type 1 interferons and/or their corresponding receptor(s)), and, optionally, a second therapeutic agent (e.g., steroids, etc.) to said mammal.

In some embodiments, biomarkers are selected from those listed in Tables 1, 2 and/or 3.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Alignment of a density plot of interferon-induced genes with a 2D hierarchical cluster heatmap of control and SLE patient samples shows a single region highly enriched in interferon-induced genes.

FIG. 2. IRGM scores from Active SLE patients are significantly higher than normal controls.

FIG. 3. Examples of SLE patients (patient X (FIG. 3A) and patient Y (FIG. 3B)) whose IRGM and anti-dsDNA levels are well correlated.

FIG. 4. Rho values of Spearman correlation of probes to the IRG signature reveal the extent of the region containing IRG signal.

FIG. 5. Three-gene combination versus 24-gene combination Pearson correlation illustrated as a histogram.

MODES FOR CARRYING OUT THE INVENTION General Techniques

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as, “Molecular Cloning: A Laboratory Manual”, second edition (Sambrook et al., 1989); “Oligonucleotide Synthesis” (M. J. Gait, ed., 1984); “Animal Cell Culture” (R. I. Freshney, ed., 1987); “Methods in Enzymology” (Academic Press, Inc.); “Current Protocols in Molecular Biology” (F. M. Ausubel et al., eds., 1987, and periodic updates); “PCR: The Polymerase Chain Reaction”, (Mullis et al., eds., 1994).

Primers, oligonucleotides and polynucleotides employed in the present invention can be generated using standard techniques known in the art.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, N.Y. 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, N.Y. 1992), provide one skilled in the art with a general guide to many of the terms used in the present application.

DEFINITIONS

The term “array” or “microarray”, as used herein refers to an ordered arrangement of hybridizable array elements, preferably polynucleotide probes (e.g., oligonucleotides), on a substrate. The substrate can be a solid substrate, such as a glass slide, or a semi-solid substrate, such as nitrocellulose membrane. The nucleotide sequences can be DNA, RNA, or any permutations thereof.

A “target sequence”, “target nucleic acid” or “target protein”, as used herein, is a polynucleotide sequence of interest, in which a mutation of the invention is suspected or known to reside, the detection of which is desired. Generally, a “template,” as used herein, is a polynucleotide that contains the target nucleotide sequence. In some instances, the terms “target sequence,” “template DNA,” “template polynucleotide,” “target nucleic acid,” “target polynucleotide,” and variations thereof, are used interchangeably.

“Amplification,” as used herein, generally refers to the process of producing multiple copies of a desired sequence. “Multiple copies” means at least 2 copies. A “copy” does not necessarily mean perfect sequence complementarity or identity to the template sequence. For example, copies can include nucleotide analogs such as deoxyinosine, intentional sequence alterations (such as sequence alterations introduced through a primer comprising a sequence that is hybridizable, but not complementary, to the template), and/or sequence errors that occur during amplification.

Expression/amount of a gene or biomarker in a first sample is at a level “greater than” the level in a second sample if the expression level/amount of the gene or biomarker in the first sample is at least about 1.5×, 1.75×, 2×, 3×, 4×, 5×, 6×, 7×, 8×, 9× or 10× the expression level/amount of the gene or biomarker in the second sample. Expression levels/amounts can be determined based on any suitable criterion known in the art, including but not limited to mRNA, cDNA, proteins, protein fragments and/or gene copy. Expression levels/amounts can be determined qualitatively and/or quantitatively.

“Polynucleotide,” or “nucleic acid,” as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, cabamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid supports. The 5′ and 3′ terminal OH can be phosphorylated or substituted with amines organic capping groups moieties of from 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2′-O-methyl-2′-O— allyl, 2′-fluoro- or 2′-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S (“thioate”), P(S)S (“dithioate”), “(O)NR 2 (“amidate”), P(O)R, P(O)OR′, CO or CH 2 (“formacetal”), in which each R or R′ is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (—O—) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

“Oligonucleotide,” as used herein, generally refers to short, generally single stranded, generally synthetic polynucleotides that are generally, but not necessarily, less than about 200 nucleotides in length. The terms “oligonucleotide” and “polynucleotide” are not mutually exclusive. The description above for polynucleotides is equally and fully applicable to oligonucleotides.

A “primer” is generally a short single stranded polynucleotide, generally with a free 3′-OH group, that binds to a target potentially present in a sample of interest by hybridizing with a target sequence, and thereafter promotes polymerization of a polynucleotide complementary to the target.

The phrase “gene amplification” refers to a process by which multiple copies of a gene or gene fragment are formed in a particular cell or cell line. The duplicated region (a stretch of amplified DNA) is often referred to as “amplicon.” Usually, the amount of the messenger RNA (mRNA) produced, i.e., the level of gene expression, also increases in the proportion of the number of copies made of the particular gene expressed.

The term “mutation”, as used herein, means a difference in the amino acid or nucleic acid sequence of a particular protein or nucleic acid (gene, RNA) relative to the wild-type protein or nucleic acid, respectively. A mutated protein or nucleic acid can be expressed from or found on one allele (heterozygous) or both alleles (homozygous) of a gene, and may be somatic or germ line.

To “inhibit” is to decrease or reduce an activity, function, and/or amount as compared to a reference.

The term “3′” generally refers to a region or position in a polynucleotide or oligonucleotide 3′ (downstream) from another region or position in the same polynucleotide or oligonucleotide. The term “5′” generally refers to a region or position in a polynucleotide or oligonucleotide 5′ (upstream) from another region or position in the same polynucleotide or oligonucleotide.

“Detection” includes any means of detecting, including direct and indirect detection.

The term “diagnosis” is used herein to refer to the identification of a molecular or pathological state, disease or condition, such as the identification of an autoimmune disorder. The term “prognosis” is used herein to refer to the prediction of the likelihood of autoimmune disorder-attributable disease symptoms, including, for example, recurrence, flaring, and drug resistance, of an autoimmune disease. The term “prediction” is used herein to refer to the likelihood that a patient will respond either favorably or unfavorably to a drug or set of drugs. In one embodiment, the prediction relates to the extent of those responses. In one embodiment, the prediction relates to whether and/or the probability that a patient will survive or improve following treatment, for example treatment with a particular therapeutic agent, and for a certain period of time without disease recurrence. The predictive methods of the invention can be used clinically to make treatment decisions by choosing the most appropriate treatment modalities for any particular patient. The predictive methods of the present invention are valuable tools in predicting if a patient is likely to respond favorably to a treatment regimen, such as a given therapeutic regimen, including for example, administration of a given therapeutic agent or combination, surgical intervention, steroid treatment, etc., or whether long-term survival of the patient, following a therapeutic regimen is likely.

The term “long-term” survival is used herein to refer to survival for at least 1 year, 5 years, 8 years, or 10 years following therapeutic treatment.

The term “increased resistance” to a particular therapeutic agent or treatment option, when used in accordance with the invention, means decreased response to a standard dose of the drug or to a standard treatment protocol.

The term “decreased sensitivity” to a particular therapeutic agent or treatment option, when used in accordance with the invention, means decreased response to a standard dose of the agent or to a standard treatment protocol, where decreased response can be compensated for (at least partially) by increasing the dose of agent, or the intensity of treatment.

“Patient response” can be assessed using any endpoint indicating a benefit to the patient, including, without limitation, (1) inhibition, to some extent, of disease progression, including slowing down and complete arrest; (2) reduction in the number of disease episodes and/or symptoms; (3) reduction in lesional size; (4) inhibition (i.e., reduction, slowing down or complete stopping) of disease cell infiltration into adjacent peripheral organs and/or tissues; (5) inhibition (i.e. reduction, slowing down or complete stopping) of disease spread; (6) decrease of auto-immune response, which may, but does not have to, result in the regression or ablation of the disease lesion; (7) relief, to some extent, of one or more symptoms associated with the disorder; (8) increase in the length of disease-free presentation following treatment; and/or (9) decreased mortality at a given point of time following treatment.

The term “interferon inhibitor” as used herein refers to a molecule having the ability to inhibit a biological function of wild type or mutated Type 1 interferon. Accordingly, the term “inhibitor” is defined in the context of the biological role of Type 1 interferon. In one embodiment, an interferon inhibitor referred to herein specifically inhibits cell signaling via the Type 1 interferon/interferon receptor pathway. For example, an interferon inhibitor may interact with (e.g. bind to) interferon alpha receptor, or with a Type 1 interferon which normally binds to interferon receptor. In one embodiment, an interferon inhibitor binds to the extracellular domain of interferon alpha receptor. In one embodiment, an interferon inhibitor binds to the intracellular domain of interferon alpha receptor. In one embodiment, an interferon inhibitor binds to Type 1 interferon. In one embodiment, the Type 1 interferon is an interferon alpha subtype. In one embodiment, the Type 1 interferon is not interferon beta. In one embodiment, the Type 1 interferon is not interferon omega. In one embodiment, interferon biological activity inhibited by an interferon inhibitor is associated with an immune disorder, such as an autoimmune disorder. An interferon inhibitor can be in any form, so long as it is capable of inhibiting interferon/receptor activity; inhibitors include antibodies (e.g., monoclonal antibodies as defined hereinbelow), small organic/inorganic molecules, antisense oligonucleotides, aptamers, inhibitory peptides/polypeptides, inhibitory RNAs (e.g., small interfering RNAs), combinations thereof, etc.

“Antibodies” (Abs) and “immunoglobulins” (Igs) are glycoproteins having the same structural characteristics. While antibodies exhibit binding specificity to a specific antigen, immunoglobulins include both antibodies and other antibody-like molecules which generally lack antigen specificity. Polypeptides of the latter kind are, for example, produced at low levels by the lymph system and at increased levels by myelomas.

The terms “antibody” and “immunoglobulin” are used interchangeably in the broadest sense and include monoclonal antibodies (e.g., full length or intact monoclonal antibodies), polyclonal antibodies, monovalent, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity) and may also include certain antibody fragments (as described in greater detail herein). An antibody can be chimeric, human, humanized and/or affinity matured.

“Antibody fragments” comprise only a portion of an intact antibody, wherein the portion preferably retains at least one, preferably most or all, of the functions normally associated with that portion when present in an intact antibody. In one embodiment, an antibody fragment comprises an antigen binding site of the intact antibody and thus retains the ability to bind antigen. In another embodiment, an antibody fragment, for example one that comprises the Fc region, retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody, such as FcRn binding, antibody half life modulation, ADCC function and complement binding. In one embodiment, an antibody fragment is a monovalent antibody that has an in vivo half life substantially similar to an intact antibody. For example, such an antibody fragment may comprise on antigen binding arm linked to an Fc sequence capable of conferring in vivo stability to the fragment.

The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

The monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)).

“Humanized” forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also the following review articles and references cited therein: Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994).

A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.

An “affinity matured” antibody is one with one or more alterations in one or more CDRs/HVRs thereof which result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody which does not possess those alteration(s). Preferred affinity matured antibodies will have nanomolar or even picomolar affinities for the target antigen. Affinity matured antibodies are produced by procedures known in the art. Marks et al. Bio/Technology 10:779-783 (1992) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR/HVR and/or framework residues is described by: Barbas et al. Proc Nat. Acad. Sci, USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al, J. Mol. Biol. 226:889-896 (1992).

The term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain which may be generated by papain digestion of an intact antibody. The Fc region may be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at about position Cys226, or from about position Pro230, to the carboxyl-terminus of the Fc region. The Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain, and optionally comprises a CH4 domain. By “Fc region chain” herein is meant one of the two polypeptide chains of an Fc region.

The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells. The term is intended to include radioactive isotopes (e.g. At²¹¹, I¹³, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³² and radioactive isotopes of Lu), chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

A “blocking” antibody or an “antagonist” antibody is one which inhibits or reduces biological activity of the antigen it binds. Such blocking can occur by any means, e.g. by interfering with protein-protein interaction such as ligand binding to a receptor. In on embodiment, blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.

An “autoimmune disease” herein is a non-malignant disease or disorder arising from and directed against an individual's own tissues. The autoimmune diseases herein specifically exclude malignant or cancerous diseases or conditions, especially excluding B cell lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hairy cell leukemia and chronic myeloblastic leukemia. Examples of autoimmune diseases or disorders include, but are not limited to, inflammatory responses such as inflammatory skin diseases including psoriasis and dermatitis (e.g. atopic dermatitis); systemic scleroderma and sclerosis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); respiratory distress syndrome (including adult respiratory distress syndrome; ARDS); dermatitis; meningitis; encephalitis; uveitis; colitis; glomerulonephritis; allergic conditions such as eczema and asthma and other conditions involving infiltration of T cells and chronic inflammatory responses; atherosclerosis; leukocyte adhesion deficiency; rheumatoid arthritis; systemic lupus erythematosus (SLE) (including but not limited to lupus nephritis, cutaneous lupus); diabetes mellitus (e.g. Type I diabetes mellitus or insulin dependent diabetes mellitis); multiple sclerosis; Reynaud's syndrome; autoimmune thyroiditis; Hashimoto's thyroiditis; allergic encephalomyelitis; Sjogren's syndrome; juvenile onset diabetes; and immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes typically found in tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis; pernicious anemia (Addison's disease); diseases involving leukocyte diapedesis; central nervous system (CNS) inflammatory disorder; multiple organ injury syndrome; hemolytic anemia (including, but not limited to cryoglobinemia or Coombs positive anemia); myasthenia gravis; antigen-antibody complex mediated diseases; anti-glomerular basement membrane disease; antiphospholipid syndrome; allergic neuritis; Graves' disease; Lambert-Eaton myasthenic syndrome; pemphigoid bullous; pemphigus; autoimmune polyendocrinopathies; Reiter's disease; stiff-man syndrome; Behcet disease; giant cell arteritis; immune complex nephritis; IgA nephropathy; IgM polyneuropathies; immune thrombocytopenic purpura (ITP) or autoimmune thrombocytopenia etc.

As used herein, “treatment” refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, methods and compositions of the invention are useful in attempts to delay development of a disease or disorder.

An “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A “therapeutically effective amount” of a therapeutic agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agent are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

As used herein, the terms “type I interferon” and “human type I interferon” are defined as all species of native human and synthetic interferon which fall within the human and synthetic interferon-α, interferon-ω and interferon-β classes and which bind to a common cellular receptor. Natural human interferon-α comprises 23 or more closely related proteins encoded by distinct genes with a high degree of structural homology (Weissmann and Weber, Prog. Nucl. Acid. Res. Mol. Biol., 33: 251 (1986); J. Interferon Res., 13: 443-444 (1993)). The human IFN-α locus comprises two subfamilies. The first subfamily consists of at least 14 functional, non-allelic genes, including genes encoding IFN-αA (IFN-α2), IFN-αB (IFN-α8), IFN-αC (IFN-α10), IFN-αD (IFN-α1), IFN-αE (IFN-α22), IFN-αF (IFN-α21), IFN-αG (IFN-α5), IFN-α16, IFN-α17, IFN-α4, IFN-α6, IFN-α7, and IFN-αH (IFN-α14), and pseudogenes having at least 80% homology. The second subfamily, α_(II) or ω, contains at least 5 pseudogenes and 1 functional gene (denoted herein as “IFN-α_(II)1” or “IFN-ω”) which exhibits 70% homology with the IFN-α genes (Weissmann and Weber (1986)). The human IFN-β is generally thought to be encoded by a single copy gene.

As used herein, the terms “first human interferon-α (hIFN-α) receptor”, “IFN-αR”, “hIFNAR1”, “IFNAR1”, and “Uze chain” are defined as the 557 amino acid receptor protein cloned by Uze et al., Cell, 60: 225-234 (1990), including an extracellular domain of 409 residues, a transmembrane domain of 21 residues, and an intracellular domain of 100 residues, as shown in FIG. 5 on page 229 of Uze et al. In one embodiment, the foregoing terms include fragments of IFNAR1 that contain the extracellular domain (ECD) (or fragments of the ECD) of IFNAR1.

As used herein, the terms “second human interferon-α (hIFN-α) receptor”, “IFN-αβR”, “hIFNAR2”, “IFNAR2”, and “Novick chain” are defined as the 515 amino acid receptor protein cloned by Domanski et al., J. Biol. Chem., 37: 21606-21611 (1995), including an extracellular domain of 217 residues, a transmembrane domain of 21 residues, and an intracellular domain of 250 residues, as shown in FIG. 1 on page 21608 of Domanski et al. In one embodiment, the foregoing terms include fragments of IFNAR2 that contain the extracellular domain (ECD) (or fragments of the ECD) of IFNAR2, and soluble forms of IFNAR2, such as IFNAR2ECD fused to at least a portion of an immunoglobulin sequence.

The term “housekeeping gene” refers to a group of genes that codes for proteins whose activities are essential for the maintenance of cell function. These genes are typically similarly expressed in all cell types. Housekeeping genes include, without limitation, ribosomal protein L19 (NP_(—)000972), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Cypl, albumin, actins (e.g. β-actin), tubulins, cyclophilin, hypoxantine phosphoribosyltransferase (HRPT), ribosomal protein L32 (NP_(—)001007075), and ribosomal protein/genes 28S (e.g., Q9Y399) and 18S.

The term “biomarker” as used herein refers generally to a molecule, including a gene, protein, carbohydrate structure, or glycolipid, the expression of which in or on a mammalian tissue or cell can be detected by standard methods (or methods disclosed herein) and is predictive, diagnostic and/or prognostic for a mammalian cell's or tissue's sensitivity to treatment regimes based on inhibition of interferons, e.g. Type 1 interferons. Optionally, the expression of such a biomarker is determined to be higher than that observed for a control/reference tissue or cell sample. Optionally, for example, the expression of such a biomarker will be determined in a PCR or FACS assay to be at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, or preferably at least about 100-fold higher in the test tissue or cell sample than that observed for a control tissue or cell sample. Optionally, the expression of such a biomarker will be determined in an IHC assay to score at least 2 or higher for staining intensity. Optionally, the expression of such a biomarker will be determined using a gene chip-based assay.

An “IRG” or “interferon response gene” or “interferon responsive gene”, as used herein, refers to one or more of the genes, and corresponding gene products, listed in Table 1, 2, 3 and/or 4. As shown herein, aberrant expression levels/amounts of one or more of these genes are correlated with a variety of autoimmune disorders. As would be evident to one skilled in the art, depending on context, the term IRG can refer to nucleic acid (e.g., genes) or polypeptides (e.g., proteins) having the designation or unique identifier listed in Table 1, 2, 3 and/or 4.

The term “sample”, as used herein, refers to a composition that is obtained or derived from a subject of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example based on physical, biochemical, chemical and/or physiological characteristics. For example, the phrase “disease sample” and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is to be characterized.

By “tissue or cell sample” is meant a collection of similar cells obtained from a tissue of a subject or patient. The source of the tissue or cell sample may be solid tissue as from a fresh, frozen and/or preserved organ or tissue sample or biopsy or aspirate; blood or any blood constituents; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject. The tissue sample may also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a disease tissue/organ. The tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like. A “reference sample”, “reference cell”, or “reference tissue”, as used herein, refers to a sample, cell or tissue obtained from a source known, or believed, not to be afflicted with the disease or condition for which a method or composition of the invention is being used to identify. In one embodiment, a reference sample, reference cell or reference tissue is obtained from a healthy part of the body of the same subject or patient in whom a disease or condition is being identified using a composition or method of the invention. In one embodiment, a reference sample, reference cell or reference tissue is obtained from a healthy part of the body of an individual who is not the subject or patient in whom a disease or condition is being identified using a composition or method of the invention.

For the purposes herein a “section” of a tissue sample is meant a single part or piece of a tissue sample, e.g. a thin slice of tissue or cells cut from a tissue sample. It is understood that multiple sections of tissue samples may be taken and subjected to analysis according to the present invention, provided that it is understood that the present invention comprises a method whereby the same section of tissue sample is analyzed at both morphological and molecular levels, or is analyzed with respect to both protein and nucleic acid.

By “correlate” or “correlating” is meant comparing, in any way, the performance and/or results of a first analysis or protocol with the performance and/or results of a second analysis or protocol. For example, one may use the results of a first analysis or protocol in carrying out a second protocols and/or one may use the results of a first analysis or protocol to determine whether a second analysis or protocol should be performed. With respect to the embodiment of gene expression analysis or protocol, one may use the results of the gene expression analysis or protocol to determine whether a specific therapeutic regimen should be performed.

The word “label” when used herein refers to a compound or composition which is conjugated or fused directly or indirectly to a reagent such as a nucleic acid probe or an antibody and facilitates detection of the reagent to which it is conjugated or fused. The label may itself be detectable (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable.

General Illustrative Techniques

A sample comprising a target molecule can be obtained by methods well known in the art, and that are appropriate for the particular type and location of the disease of interest. Tissue biopsy is often used to obtain a representative piece of disease tissue. Alternatively, cells can be obtained indirectly in the form of tissues/fluids that are known or thought to contain the disease cells of interest. For instance, samples of disease lesions may be obtained by resection, bronchoscopy, fine needle aspiration, bronchial brushings, or from sputum, pleural fluid or blood. Genes or gene products can be detected from disease tissue or from other body samples such as urine, sputum or serum. The same techniques discussed above for detection of target genes or gene products in disease samples can be applied to other body samples. Disease cells are sloughed off from disease lesions and appear in such body samples. By screening such body samples, a simple early diagnosis can be achieved for these diseases. In addition, the progress of therapy can be monitored more easily by testing such body samples for target genes or gene products.

In one embodiment, methods of the invention are useful for detecting any autoimmune disorder with which abnormal activation (e.g., overexpression) of interferons, in particular Type 1 interferons and/or their associated signaling pathway, is associated. The diagnostic methods of the present invention are useful for clinicians so that they can decide upon an appropriate course of treatment. For example, a sample from a subject displaying a high level of expression of the genes or gene products disclosed herein might suggest a more aggressive therapeutic regimen than a sample exhibiting a comparatively lower level of expression. Methods of the invention can be utilized in a variety of settings, including for example in aiding in patient selection during the course of drug development, prediction of likelihood of success when treating an individual patient with a particular treatment regimen, in assessing disease progression, in monitoring treatment efficacy, in determining prognosis for individual patients, in assessing predisposition of an individual to develop a particular autoimmune disorder (e.g., systemic lupus erythematosus, Sjogren's syndrome), in differentiating disease staging, etc.

Means for enriching a tissue preparation for disease cells are known in the art. For example, the tissue may be isolated from paraffin or cryostat sections. Disease cells may also be separated from normal cells by flow cytometry or laser capture microdissection. These, as well as other techniques for separating disease from normal cells, are well known in the art. If the disease tissue is highly contaminated with normal cells, detection of signature gene expression profile may be more difficult, although techniques for minimizing contamination and/or false positive/negative results are known, some of which are described hereinbelow. For example, a sample may also be assessed for the presence of a biomarker (including a mutation) known to be associated with a disease cell of interest but not a corresponding normal cell, or vice versa.

The invention also provides a variety of compositions suitable for use in performing methods of the invention. For example, the invention provides arrays that can be used in such methods. In one embodiment, an array of the invention comprises individual or collections of nucleic acid molecules useful for detecting mutations of the invention. For instance, an array of the invention may comprises a series of discretely placed individual nucleic acid oligonucleotides or sets of nucleic acid oligonucleotide combinations that are hybridizable to a sample comprising target nucleic acids, whereby such hybridization is indicative of presence or absence of a mutation of the invention.

Several techniques are well-known in the art for attaching nucleic acids to a solid substrate such as a glass slide. One method is to incorporate modified bases or analogs that contain a moiety that is capable of attachment to a solid substrate, such as an amine group, a derivative of an amine group or another group with a positive charge, into nucleic acid molecules that are synthesized. The synthesized product is then contacted with a solid substrate, such as a glass slide, which is coated with an aldehyde or another reactive group which will form a covalent link with the reactive group that is on the amplified product and become covalently attached to the glass slide. Other methods, such as those using amino propryl silican surface chemistry are also known in the art, as disclosed at http://www.cmt.corning.com and http://cmgm.stanford.edu/pbrown1.

Attachment of groups to oligonucleotides which could be later converted to reactive groups is also possible using methods known in the art. Any attachment to nucleotides of oligonucleotides will become part of oligonucleotide, which could then be attached to the solid surface of the microarray.

Amplified nucleic acids can be further modified, such as through cleavage into fragments or by attachment of detectable labels, prior to or following attachment to the solid substrate, as required and/or permitted by the techniques used.

Typical Methods and Materials of the Invention

The methods and assays disclosed herein are directed to the examination of expression of one or more biomarkers in a mammalian tissue or cell sample, wherein the determination of that expression of one or more such biomarkers is predictive or indicative of whether the tissue or cell sample will be sensitive to treatment based on the use of interferon inhibitors. The methods and assays include those which examine expression of biomarkers such as one or more of those listed in Table 1, 2 and/or 3.

As discussed above, there are some populations of diseased human cell types that are associated with abnormal expression of interferons such as the Type 1 interferons which is associated with various autoimmune disorders. It is therefore believed that the disclosed methods and assays can provide for convenient, efficient, and potentially cost-effective means to obtain data and information useful in assessing appropriate or effective therapies for treating patients. For example, a patient having been diagnosed with an immune related condition could have a biopsy performed to obtain a tissue or cell sample, and the sample could be examined by way of various in vitro assays to determine whether the patient's cells would be sensitive to a therapeutic agent such as an interferon inhibitor (e.g., an anti-interferon alpha antibody or an antibody to interferon alpha receptor).

The invention provides methods for predicting the sensitivity of a mammalian tissue or cells sample (such as a cell associated with an autoimmune disorder) to an interferon inhibitor. In the methods, a mammalian tissue or cell sample is obtained and examined for expression of one or more biomarkers. The methods may be conducted in a variety of assay formats, including assays detecting mRNA expression, enzymatic assays detecting presence of enzymatic activity, and immunohistochemistry assays. Determination of expression of such biomarkers in said tissues or cells will be predictive that such tissues or cells will be sensitive to the interferon inhibitor therapy. Applicants surprisingly found that the expression of such particular biomarkers correlates closely with presence and/or extent of various autoimmune disorders.

As discussed below, expression of various biomarkers in a sample can be analyzed by a number of methodologies, many of which are known in the art and understood by the skilled artisan, including but not limited to, immunohistochemical and/or Western analysis, quantitative blood based assays (as for example Serum ELISA) (to examine, for example, levels of protein expression), biochemical enzymatic activity assays, in situ hybridization, Northern analysis and/or PCR analysis of mRNAs, as well as any one of the wide variety of assays that can be performed by gene and/or tissue array analysis. Typical protocols for evaluating the status of genes and gene products are found, for example in Ausubel et al. eds., 1995, Current Protocols In Molecular Biology, Units 2 (Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting) and 18 (PCR Analysis).

The protocols below relating to detection of particular biomarkers, such as those listed in Table 1, 2 and/or 3, in a sample are provided for illustrative purposes.

Optional methods of the invention include protocols which examine or test for presence of IRG in a mammalian tissue or cell sample. A variety of methods for detecting IRG can be employed and include, for example, immunohistochemical analysis, immunoprecipitation, Western blot analysis, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting (FACS) and the like. For example, an optional method of detecting the expression of IRG in a tissue or sample comprises contacting the sample with a IRG antibody, a IRG-reactive fragment thereof, or a recombinant protein containing an antigen binding region of a IRG antibody; and then detecting the binding of IRG protein in the sample.

In particular embodiments of the invention, the expression of IRG proteins in a sample is examined using immunohistochemistry and staining protocols. Immunohistochemical staining of tissue sections has been shown to be a reliable method of assessing or detecting presence of proteins in a sample. Immunohistochemistry (“IHC”) techniques utilize an antibody to probe and visualize cellular antigens in situ, generally by chromogenic or fluorescent methods.

For sample preparation, a tissue or cell sample from a mammal (typically a human patient) may be used. Examples of samples include, but are not limited to, tissue biopsy, blood, lung aspirate, sputum, lymph fluid, etc. The sample can be obtained by a variety of procedures known in the art including, but not limited to surgical excision, aspiration or biopsy. The tissue may be fresh or frozen. In one embodiment, the sample is fixed and embedded in paraffin or the like.

The tissue sample may be fixed (i.e. preserved) by conventional methodology (See e.g., “Manual of Histological Staining Method of the Armed Forces Institute of Pathology,” 3^(rd) edition (1960) Lee G. Luna, HT (ASCP) Editor, The Blakston Division McGraw-Hill Book Company, New York; The Armed Forces Institute of Pathology Advanced Laboratory Methods in Histology and Pathology (1994) Ulreka V. Mikel, Editor, Armed Forces Institute of Pathology, American Registry of Pathology, Washington, D.C.). One of skill in the art will appreciate that the choice of a fixative is determined by the purpose for which the sample is to be histologically stained or otherwise analyzed. One of skill in the art will also appreciate that the length of fixation depends upon the size of the tissue sample and the fixative used. By way of example, neutral buffered formalin, Bouin's or paraformaldehyde, may be used to fix a sample.

Generally, the sample is first fixed and is then dehydrated through an ascending series of alcohols, infiltrated and embedded with paraffin or other sectioning media so that the tissue sample may be sectioned. Alternatively, one may section the tissue and fix the sections obtained. By way of example, the tissue sample may be embedded and processed in paraffin by conventional methodology (See e.g., “Manual of Histological Staining Method of the Armed Forces Institute of Pathology”, supra). Examples of paraffin that may be used include, but are not limited to, Paraplast, Broloid, and Tissuemay. Once the tissue sample is embedded, the sample may be sectioned by a microtome or the like (See e.g., “Manual of Histological Staining Method of the Armed Forces Institute of Pathology”, supra). By way of example for this procedure, sections may range from about three microns to about five microns in thickness. Once sectioned, the sections may be attached to slides by several standard methods. Examples of slide adhesives include, but are not limited to, silane, gelatin, poly-L-lysine and the like. By way of example, the paraffin embedded sections may be attached to positively charged slides and/or slides coated with poly-L-lysine.

If paraffin has been used as the embedding material, the tissue sections are generally deparaffinized and rehydrated to water. The tissue sections may be deparaffinized by several conventional standard methodologies. For example, xylenes and a gradually descending series of alcohols may be used (See e.g., “Manual of Histological Staining Method of the Armed Forces Institute of Pathology”, supra). Alternatively, commercially available deparaffinizing non-organic agents such as Hemo-De7 (CMS, Houston, Tex.) may be used.

Optionally, subsequent to the sample preparation, a tissue section may be analyzed using IHC. IHC may be performed in combination with additional techniques such as morphological staining and/or fluorescence in-situ hybridization. Two general methods of IHC are available; direct and indirect assays. According to the first assay, binding of antibody to the target antigen (e.g., an IRG) is determined directly. This direct assay uses a labeled reagent, such as a fluorescent tag or an enzyme-labeled primary antibody, which can be visualized without further antibody interaction. In a typical indirect assay, unconjugated primary antibody binds to the antigen and then a labeled secondary antibody binds to the primary antibody. Where the secondary antibody is conjugated to an enzymatic label, a chromogenic or fluorogenic substrate is added to provide visualization of the antigen. Signal amplification occurs because several secondary antibodies may react with different epitopes on the primary antibody.

The primary and/or secondary antibody used for immunohistochemistry typically will be labeled with a detectable moiety. Numerous labels are available which can be generally grouped into the following categories:

(a) Radioisotopes, such as ³⁵S, ¹⁴C, ¹²⁵I, ³H, and ¹³¹I. The antibody can be labeled with the radioisotope using the techniques described in Current Protocols in Immunology, Volumes 1 and 2, Coligen et al., Ed. Wiley-Interscience, New York, N.Y., Pubs. (1991) for example and radioactivity can be measured using scintillation counting.

(b) Colloidal gold particles.

(c) Fluorescent labels including, but are not limited to, rare earth chelates (europium chelates), Texas Red, rhodamine, fluorescein, dansyl, Lissamine, umbelliferone, phycocrytherin, phycocyanin, or commercially available fluorophores such SPECTRUM ORANGE7 and SPECTRUM GREEN7 and/or derivatives of any one or more of the above. The fluorescent labels can be conjugated to the antibody using the techniques disclosed in Current Protocols in Immunology, supra, for example. Fluorescence can be quantified using a fluorimeter.

(d) Various enzyme-substrate labels are available and U.S. Pat. No. 4,275,149 provides a review of some of these. The enzyme generally catalyzes a chemical alteration of the chromogenic substrate that can be measured using various techniques. For example, the enzyme may catalyze a color change in a substrate, which can be measured spectrophotometrically. Alternatively, the enzyme may alter the fluorescence or chemiluminescence of the substrate. Techniques for quantifying a change in fluorescence are described above. The chemiluminescent substrate becomes electronically excited by a chemical reaction and may then emit light which can be measured (using a chemiluminometer, for example) or donates energy to a fluorescent acceptor. Examples of enzymatic labels include luciferases (e.g., firefly luciferase and bacterial luciferase; U.S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like. Techniques for conjugating enzymes to antibodies are described in O'Sullivan et al., Methods for the Preparation of Enzyme-Antibody Conjugates for use in Enzyme Immunoassay, in Methods in Enzym. (ed. J. Langone & H. Van Vunakis), Academic press, New York, 73:147-166 (1981).

Examples of enzyme-substrate combinations include, for example:

(i) Horseradish peroxidase (HRPO) with hydrogen peroxidase as a substrate, wherein the hydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylene diamine (OPD) or 3,3′,5,5′-tetramethyl benzidine hydrochloride (TMB));

(ii) alkaline phosphatase (AP) with para-Nitrophenyl phosphate as chromogenic substrate; and

(iii) β-D-galactosidase (β-D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl-β-D-galactosidase) or fluorogenic substrate (e.g., 4-methylumbelliferyl-β-D-galactosidase).

Numerous other enzyme-substrate combinations are available to those skilled in the art. For a general review of these, see U.S. Pat. Nos. 4,275,149 and 4,318,980. Sometimes, the label is indirectly conjugated with the antibody. The skilled artisan will be aware of various techniques for achieving this. For example, the antibody can be conjugated with biotin and any of the four broad categories of labels mentioned above can be conjugated with avidin, or vice versa. Biotin binds selectively to avidin and thus, the label can be conjugated with the antibody in this indirect manner. Alternatively, to achieve indirect conjugation of the label with the antibody, the antibody is conjugated with a small hapten and one of the different types of labels mentioned above is conjugated with an anti-hapten antibody. Thus, indirect conjugation of the label with the antibody can be achieved.

Aside from the sample preparation procedures discussed above, further treatment of the tissue section prior to, during or following IHC may be desired. For example, epitope retrieval methods, such as heating the tissue sample in citrate buffer may be carried out (see, e.g., Leong et al. Appl. Immunohistochem. 4(3):201 (1996)).

Following an optional blocking step, the tissue section is exposed to primary antibody for a sufficient period of time and under suitable conditions such that the primary antibody binds to the target protein antigen in the tissue sample. Appropriate conditions for achieving this can be determined by routine experimentation. The extent of binding of antibody to the sample is determined by using any one of the detectable labels discussed above. Preferably, the label is an enzymatic label (e.g. HRPO) which catalyzes a chemical alteration of the chromogenic substrate such as 3,3′-diaminobenzidine chromogen. Preferably the enzymatic label is conjugated to antibody which binds specifically to the primary antibody (e.g. the primary antibody is rabbit polyclonal antibody and secondary antibody is goat anti-rabbit antibody).

Optionally, the antibodies employed in the IHC analysis to detect expression of an IRG are antibodies generated to bind primarily to the IRG of interest. Optionally, the anti-IRG antibody is a monoclonal antibody. Anti-IRG antibodies are readily available in the art, including from various commercial sources, and can also be generated using routine skills known in the art.

Specimens thus prepared may be mounted and coverslipped. Slide evaluation is then determined, e.g. using a microscope, and staining intensity criteria, routinely used in the art, may be employed. As one example, staining intensity criteria may be evaluated as follows:

TABLE A Staining Pattern Score No staining is observed in cells. 0 Faint/barely perceptible staining is detected in more than 10% of 1+ the cells. Weak to moderate staining is observed in more than 10% of the 2+ cells. Moderate to strong staining is observed in more than 10% of the 3+ cells.

In alternative methods, the sample may be contacted with an antibody specific for said biomarker under conditions sufficient for an antibody-biomarker complex to form, and then detecting said complex. The presence of the biomarker may be detected in a number of ways, such as by Western blotting and ELISA procedures for assaying a wide variety of tissues and samples, including plasma or serum. A wide range of immunoassay techniques using such an assay format are available, see, e.g., U.S. Pat. Nos. 4,016,043, 4,424,279 and 4,018,653. These include both single-site and two-site or “sandwich” assays of the non-competitive types, as well as in the traditional competitive binding assays. These assays also include direct binding of a labelled antibody to a target biomarker.

Sandwich assays are among the most useful and commonly used assays. A number of variations of the sandwich assay technique exist, and all are intended to be encompassed by the present invention. Briefly, in a typical forward assay, an unlabelled antibody is immobilized on a solid substrate, and the sample to be tested brought into contact with the bound molecule. After a suitable period of incubation, for a period of time sufficient to allow formation of an antibody-antigen complex, a second antibody specific to the antigen, labelled with a reporter molecule capable of producing a detectable signal is then added and incubated, allowing time sufficient for the formation of another complex of antibody-antigen-labelled antibody. Any unreacted material is washed away, and the presence of the antigen is determined by observation of a signal produced by the reporter molecule. The results may either be qualitative, by simple observation of the visible signal, or may be quantitated by comparing with a control sample containing known amounts of biomarker.

Variations on the forward assay include a simultaneous assay, in which both sample and labelled antibody are added simultaneously to the bound antibody. These techniques are well known to those skilled in the art, including any minor variations as will be readily apparent. In a typical forward sandwich assay, a first antibody having specificity for the biomarker is either covalently or passively bound to a solid surface. The solid surface is typically glass or a polymer, the most commonly used polymers being cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene. The solid supports may be in the form of tubes, beads, discs of microplates, or any other surface suitable for conducting an immunoassay. The binding processes are well-known in the art and generally consist of cross-linking covalently binding or physically adsorbing, the polymer-antibody complex is washed in preparation for the test sample. An aliquot of the sample to be tested is then added to the solid phase complex and incubated for a period of time sufficient (e.g. 2-40 minutes or overnight if more convenient) and under suitable conditions (e.g. from room temperature to 40° C. such as between 25° C. and 32° C. inclusive) to allow binding of any subunit present in the antibody. Following the incubation period, the antibody subunit solid phase is washed and dried and incubated with a second antibody specific for a portion of the biomarker. The second antibody is linked to a reporter molecule which is used to indicate the binding of the second antibody to the molecular marker.

An alternative method involves immobilizing the target biomarkers in the sample and then exposing the immobilized target to specific antibody which may or may not be labelled with a reporter molecule. Depending on the amount of target and the strength of the reporter molecule signal, a bound target may be detectable by direct labelling with the antibody. Alternatively, a second labelled antibody, specific to the first antibody is exposed to the target-first antibody complex to form a target-first antibody-second antibody tertiary complex. The complex is detected by the signal emitted by the reporter molecule. By “reporter molecule”, as used in the present specification, is meant a molecule which, by its chemical nature, provides an analytically identifiable signal which allows the detection of antigen-bound antibody. The most commonly used reporter molecules in this type of assay are either enzymes, fluorophores or radionuclide containing molecules (i.e. radioisotopes) and chemiluminescent molecules.

In the case of an enzyme immunoassay, an enzyme is conjugated to the second antibody, generally by means of glutaraldehyde or periodate. As will be readily recognized, however, a wide variety of different conjugation techniques exist, which are readily available to the skilled artisan. Commonly used enzymes include horseradish peroxidase, glucose oxidase, -galactosidase and alkaline phosphatase, amongst others. The substrates to be used with the specific enzymes are generally chosen for the production, upon hydrolysis by the corresponding enzyme, of a detectable color change. Examples of suitable enzymes include alkaline phosphatase and peroxidase. It is also possible to employ fluorogenic substrates, which yield a fluorescent product rather than the chromogenic substrates noted above. In all cases, the enzyme-labelled antibody is added to the first antibody-molecular marker complex, allowed to bind, and then the excess reagent is washed away. A solution containing the appropriate substrate is then added to the complex of antibody-antigen-antibody. The substrate will react with the enzyme linked to the second antibody, giving a qualitative visual signal, which may be further quantitated, usually spectrophotometrically, to give an indication of the amount of biomarker which was present in the sample. Alternately, fluorescent compounds, such as fluorescein and rhodamine, may be chemically coupled to antibodies without altering their binding capacity. When activated by illumination with light of a particular wavelength, the fluorochrome-labelled antibody adsorbs the light energy, inducing a state to excitability in the molecule, followed by emission of the light at a characteristic color visually detectable with a light microscope. As in the EIA, the fluorescent labelled antibody is allowed to bind to the first antibody-molecular marker complex. After washing off the unbound reagent, the remaining tertiary complex is then exposed to the light of the appropriate wavelength, the fluorescence observed indicates the presence of the molecular marker of interest. Immunofluorescence and EIA techniques are both very well established in the art. However, other reporter molecules, such as radioisotope, chemiluminescent or bioluminescent molecules, may also be employed.

It is contemplated that the above described techniques may also be employed to detect expression of IRG.

Methods of the invention further include protocols which examine the presence and/or expression of mRNAs, such as IRG mRNAs, in a tissue or cell sample. Methods for the evaluation of mRNAs in cells are well known and include, for example, hybridization assays using complementary DNA probes (such as in situ hybridization using labeled IRG riboprobes, Northern blot and related techniques) and various nucleic acid amplification assays (such as RT-PCR using complementary primers specific for IRG, and other amplification type detection methods, such as, for example, branched DNA, SISBA, TMA and the like).

Tissue or cell samples from mammals can be conveniently assayed for, e.g., IRG mRNAs using Northern, dot blot or PCR analysis. For example, RT-PCR assays such as quantitative PCR assays are well known in the art. In an illustrative embodiment of the invention, a method for detecting an IRG mRNA in a biological sample comprises producing cDNA from the sample by reverse transcription using at least one primer; amplifying the cDNA so produced using an IRG polynucleotide as sense and antisense primers to amplify IRG cDNAs therein; and detecting the presence of the amplified IRG cDNA. In addition, such methods can include one or more steps that allow one to determine the levels of IRG mRNA in a biological sample (e.g. by simultaneously examining the levels a comparative control mRNA sequence of a “housekeeping” gene such as an actin family member). Optionally, the sequence of the amplified IRG cDNA can be determined.

Material embodiments of this aspect of the invention include IRG primers and primer pairs, which allow the specific amplification of the polynucleotides of the invention or of any specific parts thereof, and probes that selectively or specifically hybridize to nucleic acid molecules of the invention or to any part thereof. Probes may be labeled with a detectable marker, such as, for example, a radioisotope, fluorescent compound, bioluminescent compound, a chemiluminescent compound, metal chelator or enzyme. Such probes and primers can be used to detect the presence of IRG polynucleotides in a sample and as a means for detecting a cell expressing IRG proteins. As will be understood by the skilled artisan, a great many different primers and probes may be prepared based on the sequences provided in herein and used effectively to amplify, clone and/or determine the presence and/or levels of IRG mRNAs.

Optional methods of the invention include protocols which examine or detect mRNAs, such as IRG mRNAs, in a tissue or cell sample by microarray technologies. Using nucleic acid microarrays, test and control mRNA samples from test and control tissue samples are reverse transcribed and labeled to generate cDNA probes. The probes are then hybridized to an array of nucleic acids immobilized on a solid support. The array is configured such that the sequence and position of each member of the array is known. For example, a selection of genes that have potential to be expressed in certain disease states may be arrayed on a solid support. Hybridization of a labeled probe with a particular array member indicates that the sample from which the probe was derived expresses that gene. Differential gene expression analysis of disease tissue can provide valuable information. Microarray technology utilizes nucleic acid hybridization techniques and computing technology to evaluate the mRNA expression profile of thousands of genes within a single experiment. (see, e.g., WO 01/75166 published Oct. 11, 2001; (See, for example, U.S. Pat. No. 5,700,637, U.S. Pat. No. 5,445,934, and U.S. Pat. No. 5,807,522, Lockart, Nature Biotechnology, 14:1675-1680 (1996); Cheung, V. G. et al., Nature Genetics 21(Suppl):15-19 (1999) for a discussion of array fabrication). DNA microarrays are miniature arrays containing gene fragments that are either synthesized directly onto or spotted onto glass or other substrates. Thousands of genes are usually represented in a single array. A typical microarray experiment involves the following steps: 1) preparation of fluorescently labeled target from RNA isolated from the sample, 2) hybridization of the labeled target to the microarray, 3) washing, staining, and scanning of the array, 4) analysis of the scanned image and 5) generation of gene expression profiles. Currently two main types of DNA microarrays are being used: oligonucleotide (usually 25 to 70 mers) arrays and gene expression arrays containing PCR products prepared from cDNAs. In forming an array, oligonucleotides can be either prefabricated and spotted to the surface or directly synthesized on to the surface (in situ).

The Affymetrix GeneChip® system is a commerically available microarray system which comprises arrays fabricated by direct synthesis of oligonucleotides on a glass surface. Probe/Gene Arrays: Oligonucleotides, usually 25 mers, are directly synthesized onto a glass wafer by a combination of semiconductor-based photolithography and solid phase chemical synthesis technologies. Each array contains up to 400,000 different oligos and each oligo is present in millions of copies. Since oligonucleotide probes are synthesized in known locations on the array, the hybridization patterns and signal intensities can be interpreted in terms of gene identity and relative expression levels by the Affymetrix Microarray Suite software. Each gene is represented on the array by a series of different oligonucleotide probes. Each probe pair consists of a perfect match oligonucleotide and a mismatch oligonucleotide. The perfect match probe has a sequence exactly complimentary to the particular gene and thus measures the expression of the gene. The mismatch probe differs from the perfect match probe by a single base substitution at the center base position, disturbing the binding of the target gene transcript. This helps to determine the background and nonspecific hybridization that contributes to the signal measured for the perfect match oligo. The Microarray Suite software subtracts the hybridization intensities of the mismatch probes from those of the perfect match probes to determine the absolute or specific intensity value for each probe set. Probes are chosen based on current information from Genbank and other nucleotide repositories. The sequences are believed to recognize unique regions of the 3′ end of the gene. A GeneChip Hybridization Oven (“rotisserie” oven) is used to carry out the hybridization of up to 64 arrays at one time. The fluidics station performs washing and staining of the probe arrays. It is completely automated and contains four modules, with each module holding one probe array. Each module is controlled independently through Microarray Suite software using preprogrammed fluidics protocols. The scanner is a confocal laser fluorescence scanner which measures fluorescence intensity emitted by the labeled cRNA bound to the probe arrays. The computer workstation with Microarray Suite software controls the fluidics station and the scanner. Microarray Suite software can control up to eight fluidics stations using preprogrammed hybridization, wash, and stain protocols for the probe array. The software also acquires and converts hybridization intensity data into a presence/absence call for each gene using appropriate algorithms. Finally, the software detects changes in gene expression between experiments by comparison analysis and formats the output into .txt files, which can be used with other software programs for further data analysis.

The expression of a selected biomarker may also be assessed by examining gene deletion or gene amplification. Gene deletion or amplification may be measured by any one of a wide variety of protocols known in the art, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA (Thomas, Proc. Natl. Acad. Sci. USA, 77:5201-5205 (1980)), dot blotting (DNA analysis), or in situ hybridization (e.g., FISH), using an appropriately labeled probe, cytogenetic methods or comparative genomic hybridization (CGH) using an appropriately labeled probe. By way of example, these methods may be employed to detect deletion or amplification of IRG genes.

Expression of a selected biomarker in a tissue or cell sample may also be examined by way of functional or activity-based assays. For instance, if the biomarker is an enzyme, one may conduct assays known in the art to determine or detect the presence of the given enzymatic activity in the tissue or cell sample.

In the methods of the present invention, it is contemplated that the tissue or cell sample may also be examined for the expression of interferons such as Type 1 interferons, and/or activation of the Type 1 interferon signaling pathway, in the sample. Examining the tissue or cell sample for expression of Type 1 interferons and/or the corresponding receptor(s), and/or activation of the Type interferon signaling pathway, may give further information as to whether the tissue or cell sample will be sensitive to an interferon inhibitor. By way of example, the IHC techniques described above may be employed to detect the presence of one of more such molecules in the sample. It is contemplated that in methods in which a tissue or sample is being examined not only for the presence of IRG, but also for the presence of, e.g., Type 1 interferon, interferon receptor(s), separate slides may be prepared from the same tissue or sample, and each slide tested with a reagent specific for each specific biomarker or receptor. Alternatively, a single slide may be prepared from the tissue or cell sample, and antibodies directed to each biomarker or receptor may be used in connection with a multi-color staining protocol to allow visualization and detection of the respective biomarkers or receptors.

Subsequent to the determination that the tissue or cell sample expresses one or more of the biomarkers indicating the tissue or cell sample will be sensitive to treatment with interferon inhibitors, it is contemplated that an effective amount of the interferon inhibitor may be administered to the mammal to treat a disorder, such as autoimmune disorder which is afflicting the mammal. Diagnosis in mammals of the various pathological conditions described herein can be made by the skilled practitioner. Diagnostic techniques are available in the art which allow, e.g., for the diagnosis or detection of autoimmune related disease in a mammal.

An interferon inhibitor can be administered in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. Optionally, administration may be performed through mini-pump infusion using various commercially available devices.

Effective dosages and schedules for administering interferon inhibitors may be determined empirically, and making such determinations is within the skill in the art. Single or multiple dosages may be employed. For example, an effective dosage or amount of interferon inhibitor used alone may range from about 1 μg/kg to about 100 mg/kg of body weight or more per day. Interspecies scaling of dosages can be performed in a manner known in the art, e.g., as disclosed in Mordenti et al., Pharmaceut. Res., 8:1351 (1991).

When in vivo administration of interferon inhibitor is employed, normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. No. 4,657,760; 5,206,344; or 5,225,212. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue.

It is contemplated that yet additional therapies may be employed in the methods. The one or more other therapies may include but are not limited to, administration of steroids and other standard of care regimens for the particular autoimmune disorder in question. It is contemplated that such other therapies may be employed as an agent separate from the interferon inhibitor.

For use in the applications described or suggested above, kits or articles of manufacture are also provided by the invention. Such kits may comprise a carrier means being compartmentalized to receive in close confinement one or more container means such as vials, tubes, and the like, each of the container means comprising one of the separate elements to be used in the method. For example, one of the container means may comprise a probe that is or can be detectably labeled. Such probe may be an antibody or polynucleotide specific for IRG gene or message, respectively. Where the kit utilizes nucleic acid hybridization to detect the target nucleic acid, the kit may also have containers containing nucleotide(s) for amplification of the target nucleic acid sequence and/or a container comprising a reporter-means, such as a biotin-binding protein, such as avidin or streptavidin, bound to a reporter molecule, such as an enzymatic, florescent, or radioisotope label.

The kit of the invention will typically comprise the container described above and one or more other containers comprising materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. A label may be present on the container to indicate that the composition is used for a specific therapy or non-therapeutic application, and may also indicate directions for either in vivo or in vitro use, such as those described above.

The kits of the invention have a number of embodiments. A typical embodiment is a kit comprising a container, a label on said container, and a composition contained within said container; wherein the composition includes a primary antibody that binds to a IRG polypeptide sequence, the label on said container indicates that the composition can be used to evaluate the presence of IRG proteins in at least one type of mammalian cell, and instructions for using the IRG antibody for evaluating the presence of IRG proteins in at least one type of mammalian cell. The kit can further comprise a set of instructions and materials for preparing a tissue sample and applying antibody and probe to the same section of a tissue sample. The kit may include both a primary and secondary antibody, wherein the secondary antibody is conjugated to a label, e.g., an enzymatic label.

Another embodiment is a kit comprising a container, a label on said container, and a composition contained within said container; wherein the composition includes a polynucleotide that hybridizes to a complement of the IRG polynucleotide under stringent conditions, the label on said container indicates that the composition can be used to evaluate the presence of IRG in at least one type of mammalian cell, and instructions for using the IRG polynucleotide for evaluating the presence of IRG RNA or DNA in at least one type of mammalian cell.

Other optional components in the kit include one or more buffers (e.g., block buffer, wash buffer, substrate buffer, etc), other reagents such as substrate (e.g., chromogen) which is chemically altered by an enzymatic label, epitope retrieval solution, control samples (positive and/or negative controls), control slide(s) etc.

The following are examples of the methods and compositions of the invention. It is understood that various other embodiments may be practiced, given the general description provided above.

EXAMPLES Example 1 Materials and Methods

Expression of IFN-alpha responsive genes (IRG's) was analyzed in data from blood—peripheral blood mononuclear cells (PBMC) from SLE patients (with active or inactive disease) and normal donors from the University Of Minnesota (Minneapolis, Minn.).

Data was produced as follows: 92 blood samples were collected on different dates from 18 patients with active SLE, 19 blood samples were collected on different dates from 5 patients with inactive SLE, and 4 blood samples were collected from 4 healthy donors. PBMC was isolated from whole blood by standard Ficoll gradient centrifugation. RNA was prepared from PBMC samples using RNA Isolation Kit from Qiagen (Valencia, Calif.) and hybridized to WHG oligonucleotide microarray chips from Agilent (Palo Alto, Calif.). Raw data was processed by standard Agilent Feature Extraction to yield Agilent log ratio data. Normal expression of genes in response to IFN-alpha was examined by isolating PBMC from healthy donors and incubating it in culture for four hours with 100 U/ml recombinant IFN-alpha, then taking samples of the cell culture at 4, 12, 28, and 52 hours following addition of IFN-alpha.

Microarray data was clustered hierarchically in two dimensions (samples and probes) using the xcluster software program (pearson on log 2 signal) on probes with both mean signal in the top 70% ile and coefficient of variability in the top 70% ile. Cluster data was viewed with the Java Treeview software program. Numerical analysis was performed with R (http://www [insert period] r-project [insert period]org/), JMP (SAS Institute, Cary, N.C.) and Excel (Microsoft, Redmond, Wash.).

Results and Analysis

Microarray clustering of all samples showed significant grouping of both samples and genes. Sample clustering showed grouping of a large fraction of SLE patients with active disease. Gene clustering showed several different tightly grouped gene subclusters with obvious biological patterns. For instance, one subcluster was highly enriched for genes known to be specific to B cells, another to neutrophils, another for antibodies, and another for IRG's. The IRG subcluster showed an interesting pattern with respect to samples: normal samples all showed low expression of IRG's, while SLE samples showed a wide range of expression that varied from normal-like to extremely high. The expression profiles of probes within a tight subcluster are very similar but not identical, and the variation between very similar profiles may be due in significant part to noise either from biological or technological sources. For instance, some genes are represented on the microarray by more than one probe, and there are several pairs of probes in the IRG subcluster area that represent the same gene's expression. In these cases, the probes clustered near to each other, sometimes immediately adjacent. Thus it appeared that a clear pattern was present and reflected in many probes, and that utilizing the data from several probes in order to mitigate the interference of noise in the data might most clearly identify the pattern. Nonetheless, the genes that were identified could be used individually as genetic identifiers that correlate with presence of disease.

Identification of Genes Highly Induced by Interferon Alpha

In order to identify genes whose expression is highly induced by the presence of interferon alpha, PBMC samples from healthy donors were treated with recombinant interferon alpha and samples of the cell cultures were subjected to Agilent WHG expression analysis as described above. Log ratio data from these hybridizations were analyzed by two-way ANOVA (time and treatment), and 142 probes were identified by filtering of treatment p-value <5×10⁻⁷. This set of genes is a subset of genes whose expression is induced by interferon alpha, and it constitutes an effective tool for identifying clusters of genes in other experiments whose common basis for co-clustering is induction by interferon alpha.

Development of a Metric that Correlates with Disease, and Identification of Individual Genes that May Constitute Such Metric

The pattern of transcriptional activation in IRG's was measured by calculating a single metric proportional to the Agilent ratio levels of the specific subgroup of probes. For example, we describe this approach below with the IRG probes. The pattern (the aggregate profile of IRG's) was first defined by aligning a density plot of probes induced by interferon alpha in PBMC samples with the cluster heatmap of SLE and control samples (FIG. 1). Probes were defined as IRG's by starting from the two most highly correlated probes and expanding the set by adding the next most highly correlated probe or branch of probes until the set of probes appeared to contain most of the expression signature evident in its center but not so far that it contains a significant contribution from a different signature. The set is comprised of the thirty-five probes listed in Table 1.

The expression data of this group was then transformed into z-scores (mean scaled to 1, base-2 log transformed, then scaled to a standard deviation of the mean of 1), and the correlation coefficient of each probe's profile to the mean profile was calculated. These correlation coefficients were used as weighting factors to weight relatively heavily the probes that showed the strongest match to the trend of the group, and to weight relatively lightly those that apparently were more affected by other inputs or noise.

The factors required to scale probes to 1 were multiplied by the weighting factor, to produce a composite factor that could yield a normalized, weighted metric for a single hybridization. The normal blood samples' signatures were multiplied by that factor, averaged across both probes and samples, and this number was inverted to yield a global scaling factor that would transform the output of the average of probes from a sample into a metric that would be expected to be 1 for samples from healthy donors. Each normalization/weighting factor was multiplied by this factor. The result was a vector of scalar values that were multiplied by a sample expression signature and averaged to yield the Type I Interferon Response Gene Metric (IRGM), a single metric measuring the level of IFN-alpha transcriptional response in a sample.

IRGM scores were calculated and evaluated for the set of clinical samples used for selection of the IRGM genes. IRGM scores were significantly higher for patients suffering from active SLE than healthy patients (FIG. 2).

Clinical measures of SLE disease activity and severity such as SLEDAI quantitate patient disease symptoms and may correlate with expression of genes that underlie the etiology of the disease. In order to investigate this hypothesis, IRGM data on individual patients were compared to those patients' clinical scores and lab test results. No significant correlation was observed between IRGM and SLEDAI, but the titer of anti-dsDNA antibodies in serum correlated well with IRGM in many patients with active SLE (FIG. 3). This correlation could be the basis of either assay being a surrogate for the other. It also illustrates a biological relationship that could serve as a basis for a rational design of therapy for SLE.

The IRGM test, and expression of the genes that make up such a test (as set forth in Table 1), could be useful for selecting patients that would benefit from IFN-α-based treatment for autoimmune disorders (e.g., SLE) by identifying patients that have a relatively high IRGM score and thus have IFN-α signaling that could be blocked. Equivalently, it could be used to predict that certain patients would not benefit from IFN-α-based treatment because they do not exhibit a high IRGM score and thus are not currently experiencing active IFN-α signaling that could be disrupted.

The IRGM test, and expression of the genes that make up such a test (as set forth in Table 1), are useful indicators in a variety of drug development, diagnostic, prognostic and therapeutic settings as described above. For example, this information could be used to check whether patients that have responded well to anti-IFN-α treatment had high levels of expression of the signaling targets of IFN-α before treatment and afterwards whether the treatment abrogated that expression. It would be a useful gauge of the extent to which a particular treatment affects the IFN-α signaling pathway. It might be a useful bio- or pharmacodynamic marker, measuring the profile of the effects of treatment over time.

Other Interferons

The metric-based approach described above could be utilized in a variety of ways in characterizing disease pathways, mechanisms of action and drug pharmacodynamics. For example, different interferon molecules probably have different properties that the IRGM and/or a test made the same way based on different microarray data and/or analyses could help measure and elucidate. For instance:

1) Type I interferons all signal through the same heterodimeric receptor but may differ in their half-life, receptor affinity, or power to initiate signaling in a target cell. These differences in magnitudes might be measured easily and accurately by IRGM. This sort of measurement could be carried out either in a cell culture experiment or in a clinical setting. Likewise, the effect of candidate drugs or drugs used in clinical settings can be gauged using this approach.

2) Different IRGM-like tests could be constructed by microarray assays of cultured blood samples treated with different interferons. To the extent to which the tests differ from each other, they could be applied to clinical samples to determine the relative activities of different interferons and/or drugs.

Other Signatures

The method used to generate the IRGM test could also be applied to any sort of expression signature, either of a state or activity of cells or of a type of cell or cells. For instance, some SLE patients show marked upmodulation of immunoglobulin gene expression, an indicator of the production of antibodies by plasma cells. Microarray probes reporting expression of these genes could collectively support the calculation of a measurement of the overall level of plasma cell activity and antibody production. In another example, there are particular transcriptional changes associated with active mitotic cell replication. These transcriptional changes could be consolidated into a test that would be applied to a variety of biological samples to measure how actively they are dividing. Or in yet another example, the genes whose expression is specific to particular types of immune cells could be categorized by which cell type expresses them and then for each cell type a test could be made. This collection of tests could then be applied to any of a variety of clinical samples (blood from SLE patients, intestinal biopsies from Crohn's Disease patients, etc.) to determine the balance of immune cell types.

TABLE 1 Agilent WHG probes constituting a set of IRG's for WHG analysis. Thirty five probes are listed, representing twenty nine unique genes. Refseq or Genbank accession numbers, symbols and names of genes are also indicated. probeid accession gene symbol gene description A_24_P343929 NM_001032731 OAS2 2′-5′-oligoadenylate synthetase 2 A_24_P395966 NM_030776 ZBP1 Z-D binding protein 1 A_23_P259141 NM_030776 ZBP1 Z-D binding protein 1 A_23_P139786 NM_003733 OASL 2′-5′-oligoadenylate synthetase-like A_24_P316965 NM_080657 RSAD2 (CIG5) radical S-adenosyl methionine domain containing 2 A_23_P17663 NM_002462 MX1 myxovirus resistance 1 A_24_P378019 NM_001572 IRF7 interferon regulatory factor 7 A_23_P64828 NM_001032409 OAS1 2′,5′-oligoadenylate synthetase 1 A_24_P943205 NM_001002264 EPSTI1 epithelial stromal interaction 1 A_23_P23074 NM_006417 IFI44 interferon-induced protein 44 A_23_P45871 NM_006820 IFI44L interferon-induced protein 44-like A_23_P819 NM_005101 G1P2 interferon, alpha-inducible protein IFI-15K A_24_P28722 NM_080657 RSAD2 (CIG5) radical S-adenosyl methionine domain containing 2 A_24_P917810 NM_000059 BRCA2 breast cancer 2, early onset A_23_P52266 NM_001001887 IFIT1 interferon-induced protein with tetratricopeptide repeats 1 A_23_P110196 NM_016323 HERC5 hect domain and RLD 5 A_23_P47955 NM_006187 OAS3 2′-5′-oligoadenylate synthetase 3 A_23_P35412 NM_001031683 IFIT3 interferon-induced protein with tetratricopeptide repeats 3 A_24_P557479 NM_017523 HSXIAPAF1 XIAP associated factor-1 A_23_P4283 NM_017523 HSXIAPAF1 XIAP associated factor-1 A_32_P132206 NM_017414 USP18 ubiquitin specific peptidase 18 A_24_P317762 NM_002346 RIG-E lymphocyte antigen 6 complex, locus E A_24_P316257 NM_145270 FLJ36208 hypothetical protein FLJ36208 A_23_P105794 NM_001002264 EPSTI1 epithelial stromal interaction 1 A_23_P166797 NM_022147 TMEM7 28 kD interferon responsive protein A_23_P111804 NM_022750 PARP12 poly (ADP-ribose) polymerase family, member 12 A_23_P250353 NM_001013000 HERC6 hect domain and RLD 6, transcript variant 3 A_24_P334361 NM_017631 SGRA12061 hypothetical protein FLJ20035 A_23_P384355 NM_207315 TYKI thymidylate kinase family LPS-inducible A_24_P30194 NM_012420 IFIT5 interferon-induced protein with tetratricopeptide repeats 5 A_23_P4286 NM_017523 HSXIAPAF1 XIAP associated factor-1, transcript variant 1 A_32_P227059 AA977193 (no symbol) (no known gene) A_23_P142750 NM_002759 EIF2AK2 eukaryotic translation initiation factor 2- alpha kinase 2 A_24_P161018 NM_017554 PARP14 poly (ADP-ribose) polymerase family, member 14 A_24_P335305 NM_006187 OAS3 2′-5′-oligoadenylate synthetase 3

Example 2 Materials and Methods

Expression of IFN-alpha responsive genes (IRG's) was analyzed in data from white blood cells (WBC) from SLE patients and healthy donors obtained by Gene Logic Inc. (Gaithersburg, Md.).

Data was produced as follows: 72 blood samples were collected from patients with active SLE, 46 blood samples were collected from healthy donors. RNA was prepared from WBC samples using RNA Isolation Kit from Qiagen (Valencia, Calif.) and hybridized to HGU133 oligonucleotide microarray chips from Affymetrix, Inc. (Santa Clara, Calif.). Raw data was processed by Affymetrix MAS5.0 feature extraction to yield Signal data.

Microarray data was clustered hierarchically in two dimensions (samples and probes) using the xcluster software program (pearson on log 2 signal) on probes with both mean signal in the top 70% ile and coefficient of variability in the top 70% ile. Cluster data was viewed with the Java Treeview software program. Numerical analysis was performed with R (http://www [insert period] r-project [insert period] org/), JMP (SAS Institute, Cary, N.C.).

Results and Analysis

Microarray clustering of all samples showed significant grouping of both samples and genes. Sample clustering showed grouping of a large fraction of SLE patients with active disease. Gene clustering showed several different tightly grouped gene subclusters with obvious biological patterns. For instance, one subcluster was highly enriched for genes known to be specific to B cells, another to neutrophils, another for antibodies, and another for IRG's. The IRG subcluster showed an interesting pattern with respect to samples: normal samples all showed low expression of IRG's, while SLE samples showed a wide range of expression that varied from normal-like to extremely high.

The expression profiles of probes within a tight subcluster were very similar but not identical, and the variation between very similar profiles may be due in significant part to noise either from biological or technological sources. For instance, some genes were represented on the microarray by more than one probe, and there were several pairs of probes in the IRG subcluster area that represent the same gene's expression. In these cases, the probes clustered near to each other, sometimes immediately adjacent. Thus it appeared that a clear pattern was present and reflected in many probes, and that utilizing the data from several probes in order to mitigate the interference of noise in the data might most clearly identify the pattern. Nonetheless, the genes that were identified could be used individually as genetic identifiers that correlate with presence of disease.

A relatively complete set of genes whose expression is indicative of a response to type 1 interferons (IRG) was identified. The IRG region, identified as a tightly clustered region of the clustered data containing 80 microarray probes highly enriched in known IRG's, was used as the definition of an interferon response profile by averaging the clustered data in this slice of 80 probes. The averaging was performed by taking the arithmetic mean across the 80 probes to yield a vector of length 118 that described the average relative interferon response in the 118 samples analyzed. The similarity of each probe in the cluster data was then compared to this signature vector by computing the Spearman correlation rho value of each pairwise comparison. Visual inspection of these rho values for probes in their clustered order showed an obvious maximum at the center of the IRG cluster (FIG. 4), and it also revealed clear boundaries between the region of locally elevated correlation and the adjacent regions that were less correlated and were influenced much more heavily by other signals and noise. The probes in this complete IRG region are listed in Table 2. Table 3 shows probes (in some cases, multiple probes) corresponding to a subset of novel genes from Table 2.

All probes in this set and their corresponding genes are useful markers for the level of response of blood cells to type I interferons. They are informative of the response individually or when combined in any number and combination as previously described to create an interferon signature metric (ISM). The measurement of their expression level for this purpose could be accomplished effectively using any of a variety of standard techniques, e.g., expression microarrays (e.g. commercially available arrays such as Affymetrix HGU133), or real-time PCR (e.g. Taqman).

TABLE 2 201 microarray probes constituting a set of type-I interferon responsive genes, their Spearman (rho) correlation to the interferon signature, Refseq or Genbank accession number, symbol, and name. Probe Rho Accession Symbol Name 226603_at 0.9760 NM_152703 SAMD9L sterile alpha motif domain containing 9- like 230036_at 0.9754 NM_152703 SAMD9L sterile alpha motif domain containing 9- like 226702_at 0.9747 NM_207315 TYKI Thymidylate kinase family LPS-inducible 242625_at 0.9733 NM_080657 RSAD2 (CIG5) radical S-adenosyl methionine domain containing 2 223220_s_at 0.9725 NM_031458 PARP9 poly ADP-ribose polymerase family, member 9 213797_at 0.9679 NM_080657 RSAD2 (CIG5) radical S-adenosyl methionine domain containing 2 204747_at 0.9664 NM_001031683 IFIT3 interferon-induced protein with tetratricopeptide repeats 3 203153_at 0.9586 NM_001001887 IFIT1 interferon-induced protein with tetratricopeptide repeats 1 226757_at 0.9582 NM_001547 IFIT2 interferon-induced protein with tetratricopeptide repeats 2 229450_at 0.9572 NM_001031683 IFIT3 interferon-induced protein with tetratricopeptide repeats 3 208436_s_at 0.9568 NM_001572 IRF7 interferon regulatory factor 7 219062_s_at 0.9544 NM_017742 ZCCHC2 zinc finger, CCHC domain containing 2 224701_at 0.9531 NM_017554 PARP14 poly ADP-ribose polymerase family, member 14 205483_s_at 0.9511 NM_005101 G1P2 interferon, alpha-inducible protein clone IFI-15K 218943_s_at 0.9495 NM_014314 DDX58 (RIG1) DEAD Asp-Glu-Ala-Asp box polypeptide 58 219863_at 0.9462 NM_016323 HERC5 hect domain and RLD 5 227609_at 0.9458 NM_001002264 EPSTI1 epithelial stromal interaction 1 breast 219356_s_at 0.9456 NM_016410 CHMP5 chromatin modifying protein 5 203596_s_at 0.9456 NM_012420 IFIT5 interferon-induced protein with tetratricopeptide repeats 5 228152_s_at 0.9422 XM_037817 LCGE22799 FLJ31033 228531_at 0.9417 NM_017654 SAMD9 sterile alpha motif domain containing 9 203595_s_at 0.9406 NM_012420 IFIT5 interferon-induced protein with tetratricopeptide repeats 5 202446_s_at 0.9383 NM_021105 PLSCR2 phospholipid scramblase 2 228617_at 0.9379 NM_017523 HSXIAPAF1 XIAP associated factor-1 232222_at 0.9374 NM_017742 ZCCHC2 zinc finger, CCHC domain containing 2 204439_at 0.9356 NM_006820 IFI44L interferon-induced protein 44-like 212657_s_at 0.9346 NM_000577 IL1RN interleukin 1 receptor antagonist 210797_s_at 0.9341 NM_003733 OASL 2′-5′-oligoadenylate synthetase-like 213294_at 0.9334 P_ADB12769 PRKR dsRNA-dependent protein kinase 211012_s_at 0.9311 NM_002675 PML promyelocytic leukemia 202086_at 0.9302 NM_002462 MX1 myxovirus influenza virus resistance 1 223502_s_at 0.9300 NM_006573 TNFSF13B tumor necrosis factor ligand superfamily, member 13b 227807_at 0.9295 NM_031458 PARP9 poly ADP-ribose polymerase family, member 9 214453_s_at 0.9278 NM_006417 IFI44 interferon-induced protein 44 205660_at 0.9275 NM_003733 OASL 2′-5′-oligoadenylate synthetase-like 228230_at 0.9273 NM_033405 PRIC285 peroxisomal proliferator-activated receptor A 218400_at 0.9253 NM_006187 OAS3 2′-5′-oligoadenylate synthetase 3 223501_at 0.9227 NM_006573 TNFSF13B tumor necrosis factor ligand superfamily, member 13b 214059_at 0.9186 NM_006417 IFI44 interferon-induced protein 44 202687_s_at 0.9178 NM_003810 Apo-2L Apo-2 Ligand 202863_at 0.9176 NM_003113 SP140 SP140 nuclear body protein 217502_at 0.9158 NM_001547 IFIT2 interferon-induced protein with tetratricopeptide repeats 2 218085_at 0.9130 NM_016410 CHMP5 chromatin modifying protein 5 228439_at 0.9123 NM_138456 BATF2 basic leucine zipper transcription factor, ATF-like 2 209593_s_at 0.9089 NM_014506 TOR1B torsin family 1, member B torsin B 222793_at 0.9079 NM_014314 DDX58 (RIG1) DEAD Asp-Glu-Ala-Asp box polypeptide 58 204994_at 0.9061 NM_002463 MX2 myxovirus influenza virus resistance 2 mouse 219691_at 0.9029 NM_017654 SAMD9 sterile alpha motif domain containing 9 208087_s_at 0.9027 NM_030776 ZBP1 Z-D binding protein 1 202270_at 0.9008 NM_002053 GBP1 guanylate binding protein 1, interferon- inducible, 67 kDa 231577_s_at 0.9007 NM_002053 GBP1 guanylate binding protein 1, interferon- inducible, 67 kDa 219209_at 0.9004 NM_022168 IFIH1 interferon induced with helicase C domain 1 200986_at 0.8978 NM_000062 SERPING1 Serine/cysteine proteinase inhibitor, clade G C1 inhibitor, 1 204972_at 0.8964 NM_001032731 OAS2 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 242020_s_at 0.8948 NM_030776 ZBP1 Z-D binding protein 1 209498_at 0.8933 NM_001024912 CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1 235276_at 0.8931 NM_001002264 EPSTI1 epithelial stromal interaction 1 breast 219211_at 0.8925 NM_017414 USP18 ubiquitin specific protease 41 239277_at 0.8897 NM_001033583 ACOT9 acyl-CoA thioesterase 9 243271_at 0.8892 NM_152703 SAMD9L sterile alpha motif domain containing 9- like 205098_at 0.8887 NM_001295 CCR1 chemokine C-C motif receptor 1 202430_s_at 0.8859 NM_021105 PLSCR2 phospholipid scramblase 2 209417_s_at 0.8837 NM_005533 IFI35 interferon-induced protein 35 205552_s_at 0.8789 NM_001032409 OAS1 2′,5′-oligoadenylate synthetase 1, 40/46 kDa 231769_at 0.8783 NM_018438 FBXO6 F-box protein 6 241916_at 0.8782 NM_021105 PLSCR2 phospholipid scramblase 2 233425_at 0.8778 NM_017742 ZCCHC2 zinc finger, CCHC domain containing 2 218543_s_at 0.8762 NM_022750 PARP12 poly ADP-ribose polymerase family, member 12 202307_s_at 0.8742 NM_000593 TAP1 transporter 1, ATP-binding cassette, sub- family B 204698_at 0.8735 NM_002201 ISG20 interferon stimulated gene 20 kDa 202269_x_at 0.8730 NM_002053 GBP1 guanylate binding protein 1, interferon- inducible, 67 kDa 232666_at 0.8711 NM_006187 OAS3 2′-5′-oligoadenylate synthetase 3, 100 kDa 218986_s_at 0.8703 NM_017631 SGRA12061 Hypothetical protein FLJ20035 FLJ20035 205569_at 0.8675 NM_014398 LAMP3 lysosomal-associated membrane protein 3 202145_at 0.8672 NM_002346 LY6E (RIGE) lymphocyte antigen 6 complex, locus E 219352_at 0.8671 NM_001013000 HERC6 hect domain and RLD 6 239979_at 0.8665 NM_001002264 EPSTI1 epithelial stromal interaction 1 breast 223599_at 0.8664 NM_001003818 TRIMP1 tripartite motif-containing pseudogene 1 230866_at 0.8656 NM_006639 CYSLTR1 cysteinyl leukotriene receptor 1 216565_x_at 0.8650 XM_497663 LOC391020 similar to Interferon-induced transmembrane protein 3 212659_s_at 0.8635 NM_000577 IL1RN interleukin 1 receptor antagonist 202869_at 0.8634 NM_001032409 OAS1 2′,5′-oligoadenylate synthetase 1, 40/46 kDa 223952_x_at 0.8623 NM_005771 DHRS9 dehydrogenase/reductase SDR family member 9 205241_at 0.8614 NM_001953 SCO2 SCO cytochrome oxidase deficient homolog 2 yeast 227458_at 0.8601 NM_014143 PDL1/B7-H1 programmed cell death 1 ligand 1 231747_at 0.8600 NM_006639 CYSLTR1 cysteinyl leukotriene receptor 1 209969_s_at 0.8576 NM_007315 STAT1 signal transducer and activator of transcription 1, 91 kDa 218999_at 0.8561 NM_018295 AGPR4538 hypothetical protein MGC5242 224009_x_at 0.8535 NM_005771 DHRS9 dehydrogenase/reductase SDR family member 9 228607_at 0.8529 NM_001032731 OAS2 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 205099_s_at 0.8516 NM_001295 CCR1 chemokine C-C motif receptor 1 219799_s_at 0.8479 NM_005771 DHRS9 dehydrogenase/reductase SDR family member 9 206133_at 0.8420 NM_017523 HSXIAPAF1 XIAP associated factor-1 211889_x_at 0.8386 NM_001024912 CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1 222154_s_at 0.8365 NM_015535 DNAPTP6 DNA polymerase-transactivated protein 6 225291_at 0.8350 NM_033109 PNPT1 polyribonucleotide nucleotidyltransferase 1 202864_s_at 0.8347 NM_003113 SP140 SP140 nuclear body protein 210705_s_at 0.8341 NM_033034 TRIM5 tripartite motif-containing 5 223167_s_at 0.8334 NM_013396 USP25 ubiquitin specific protease 25 229625_at 0.8324 NM_004120 GBP5 guanylate binding protein 5 202837_at 0.8278 NM_006700 TRAFD1 TRAF-type zinc finger domain containing 1 216243_s_at 0.8185 NM_000577 IL1RN interleukin 1 receptor antagonist 223849_s_at 0.8180 NM_020963 MOV10 Mov10, Moloney leukemia virus 10, homolog mouse 222498_at 0.8175 NM_022461 AZI2 5-azacytidine induced 2 238581_at 0.8173 NM_004120 GBP5 guanylate binding protein 5 217933_s_at 0.8138 NM_015907 LAP3 leucine aminopeptidase 3 219519_s_at 0.8108 NM_023068 SIGLEC1 sialoadhesin 208392_x_at 0.8084 NM_004509 SP110 SP110 nuclear body protein 239988_at 0.8079 NM_017912 SKKS30637 Hect domain and RLD 6 230314_at 0.8074 P_ADH28842 CMLM110 chronic myclogenous leukaemia (CML) gene marker #110 206576_s_at 0.8072 NM_001024912 CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1 227347_x_at 0.8047 NM_021170 HES4 hairy and enhancer of split 4 Drosophila 202411_at 0.8038 NM_005532 IFI27 interferon, alpha-inducible protein 27 219684_at 0.7998 NM_022147 TMEM7 transmembrane protein 7 205003_at 0.7974 NM_014705 DOCK4 dedicator of cytokinesis 4 212185_x_at 0.7969 NM_005953 MT2A metallothionein 2A 235256_s_at 0.7957 NM_138801 GALM galactose mutarotase aldose 1-epimerase 242234_at 0.7948 NM_017523 HSXIAPAF1 XIAP associated factor-1 211883_x_at 0.7916 NM_001024912 CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1 206513_at 0.7891 NM_004833 AIM2 absent in melanoma 2 44673_at 0.7884 NM_023068 SIGLEC1 sialoadhesin 209546_s_at 0.7869 NM_003661 APOL1 apolipoprotein L, 1 204415_at 0.7838 NM_002038 G1P3 interferon, alpha-inducible protein clone IFI-6-16 206553_at 0.7821 NM_001032731 OAS2 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 206461_x_at 0.7758 NM_005946 MT2A metallothionein 2A 226169_at 0.7746 NM_030962 SBF2 SET binding factor 2 244398_x_at 0.7742 NM_152373 ZNF684 zinc finger protein 684 238439_at 0.7659 NM_144590 ANKRD22 ankyrin repeat domain 22 227649_s_at 0.7646 NM_015326 SRGAP2 SLIT-ROBO Rho GTPase activating protein 2 220998_s_at 0.7644 NM_030930 UNC93B1 unc-93 homolog B1 C. elegans 204211_x_at 0.7628 NM_002759 EIF2AK2 eukaryotic translation initiation factor 2- alpha kinase 2 224973_at 0.7612 NM_017633 FAM46A family with sequence similarity 46, member A 234974_at 0.7601 NM_138801 GALM galactose mutarotase aldose 1-epimerase 242898_at 0.7588 NM_002759 EIF2AK2 eukaryotic translation initiation factor 2- alpha kinase 2 232034_at 0.7581 BC080605 LOC203274 hypothetical protein LOC203274 231455_at 0.7560 NM_001001695 FLJ42418 FLJ42418 208581_x_at 0.7546 NM_005952 MT1X metallothionein 1X 224225_s_at 0.7545 NM_016135 ETV7 ets variant gene 7 (TEL2 oncogene) 205875_s_at 0.7543 NM_016381 TREX1 three prime repair exonuclease 1 209286_at 0.7522 NM_006449 CDC42EP3 CDC42 effector protein Rho GTPase binding 3 205715_at 0.7472 NM_004334 BST1 bone marrow stromal cell antigen 1 223834_at 0.7465 NM_014143 PDL1/B7-H1 programmed cell death 1 ligand 1 212285_s_at 0.7414 NM_198576 AGRN agrin 230695_s_at 0.7381 NM_152732 C6orf206 chromosome 6 open reading frame 206 219364_at 0.7381 NM_024119 LGP2 likely ortholog of mouse D11lgp2 238455_at 0.7371 NM_032812 PLXDC2 Plexin domain containing 2 201641_at 0.7343 NM_004335 BST2 Bone marrow stromal antigen 2 219439_at 0.7273 NM_020156 C1GALT1 core 1 synthase, glyc-N-acetylgal 3-beta- galtransferase, 1 224503_s_at 0.7231 NM_017742 ZCCHC2 zinc finger, CCHC domain containing 2 234942_s_at 0.7226 NM_052951 DNTTIP1 deoxynucleotidyltransferase, terminal, interacting protein 1 214933_at 0.7212 NM_000068 CAC1A calcium channel, voltage-dependent, P/Q type, alpha 1A 219055_at 0.7189 NM_018079 SRBD1 S1 RNA binding domain 1 225447_at 0.7179 NM_000408 GPD2 glycerol-3-phosphate dehydrogenase 2 mitochondrial 236285_at 0.7173 P_AAF17573 SYN22A2 Breast cancer associated SYN22A2 coding sequence 217165_x_at 0.7168 NM_005946 MT2A metallothionein 2A 200923_at 0.7164 NM_005567 LGALS3BP lectin, galactoside-binding, soluble, 3 binding protein 220104_at 0.7159 NM_020119 ZC3HAV1 zinc finger CCCH-type, antiviral 1 216950_s_at 0.7133 NM_000566 FCGR1A Fc fragment of IgG, high affinity Ia, receptor CD64 227905_s_at 0.7115 NM_022461 AZI2 5-azacytidine induced 2 230997_at 0.7109 NM_145755 TTC21A tetratricopeptide repeat domain 21A 210889_s_at 0.7099 NM_001002273 FCGR2B Low affinity immunoglobulin gamma fc receptor ii-b 214511_x_at 0.7050 NM_000566 FCGR1A Fc fragment of IgG, high affinity Ia, receptor (CD64) 211456_x_at 0.7045 NM_001039954 MT1P2 metallothionein 1 pseudogene 2 232563_at 0.7017 NM_152373 ZNF684 zinc finger protein 684 235456_at 0.6926 NM_021063 HIST1H2BD histone 1, H2bd 229194_at 0.6917 NM_032373 PCGF5 polycomb group ring finger 5 235157_at 0.6859 NM_017554 PARP14 poly ADP-ribose polymerase family, member 14 230333_at 0.6851 NM_002970 SAT Spermidine/spermine N1- acetyltransferase 231956_at 0.6813 NM_020954 KIAA1618 KIAA1618 235175_at 0.6803 NM_052941 GBP4 guanylate binding protein 4 232149_s_at 0.6777 NM_003580 NSMAF neutral sphingomyelinase N-SMase activation assoc factor 235331_x_at 0.6769 NM_032373 PCGF5 polycomb group ring finger 5 221653_x_at 0.6762 NM_030882 APOL2 apolipoprotein L, 2 219716_at 0.6689 NM_030641 APOL6 apolipoprotein L, 6 214909_s_at 0.6669 NM_013974 DDAH2 dimethylarginine dimethylaminohydrolase 2 207500_at 0.6654 NM_004347 CASP5 caspase 5, apoptosis-related cysteine protease 232081_at 0.6648 NM_004915 ABCG1 ATP-binding cassette, sub-family G WHITE, member 1 241812_at 0.6584 NM_015535 DNAPTP6 DNA polymerase-transactivated protein 6 230166_at 0.6571 NM_133465 KIAA1958 KIAA1958 239143_x_at 0.6554 NM_016271 RNF138 ring finger protein 138 217823_s_at 0.6543 NM_016021 UBE2J1 ubiquitin-conjugating enzyme E2, J1 UBC6 homolog, yeast 242109_at 0.6501 NM_006519 TCTEL1 t-complex-associated-testis-expressed 1- like 1 206175_x_at 0.6420 NM_013360 ZNF230 zinc finger protein 230 215537_x_at 0.6366 NM_013974 DDAH2 dimethylarginine dimethylaminohydrolase 2 220252_x_at 0.6318 NM_025159 CXorf21 chromosome X open reading frame 21 227268_at 0.6213 NM_016125 PLFL4625 PTD016 protein 216336_x_at 0.6153 NM_153341 IBRDC3 IBR domain containing 3 229804_x_at 0.6077 NM_018491 CBWD1 COBW domain containing 1 236013_at 0.6011 NM_000721 CAC1E calcium channel, voltage-dependent, alpha 1E subunit 227004_at 0.5968 NM_003159 CDKL5 cyclin-dependent kinase-like 5 226099_at 0.5788 NM_012081 ELL2 elongation factor, R polymerase II, 2 227947_at 0.5761 NM_014721 PHACTR2 phosphatase and actin regulator 2 210985_s_at 0.5722 NM_003113 SP140 SP140 nuclear body protein 204326_x_at 0.5699 NM_005952 MT1X metallothionein 1X 233264_at 0.5515 AK022088 FLJ12026 HEMBB1001816 212859_x_at 0.5285 NM_005953 MT1X metallothionein 1X 235348_at 0.5251 NM_032859 C13orf6 chromosome 13 open reading frame 6 225872_at 0.5053 NM_025181 SLC35F5 solute carrier family 35, member F5 235681_at 0.4913 NM_021063 HIST1H2BD histone 1, H2bd 207291_at 0.4851 NM_024081 PRRG4 proline rich Gla G-carboxyglutamic acid 4 transmembrane 234997_x_at 0.4617 CD684982 EST1502 human spermidine/spermine N1 acetyl transferase

TABLE 3 Selected subset of novel probesets/genes from Table 2. Where appropriate, multiple probesets (with their respective rho values) are listed with their respective corresponding gene. Probe Rho Accession Symbol Name 228152_s_at 0.9422 XM_037817 LCGE22799 FLJ31033 202446_s_at; 0.9383; NM_021105 PLSCR2 phospholipid scramblase 2 202430_s_at; 0.8859; 241916_at 0.8782 213294_at 0.9334 P_ADB12769 PRKR dsRNA-dependent protein kinase 211012_s_at 0.9311 NM_002675 PML promyelocytic leukemia 228230_at 0.9273 NM_033405 PRIC285 peroxisomal proliferator- activated receptor A 202687_s_at 0.9178 NM_003810 Apo-2L Apo-2 Ligand 202863_at; 0.9176; NM_003113 SP140 SP140 nuclear body protein 202864_s_at; 0.8347; 210985_s_at 0.5722 209498_at; 0.8933; NM_001024912 CEACAM1 carcinoembryonic antigen- 211889_x_at; 0.8386; related cell adhesion molecule 1 206576_s_at; 0.8072; 211883_x_at 0.7916 239277_at 0.8897 NM_001033583 ACOT9 acyl-CoA thioesterase 9 231769_at 0.8783 NM_018438 FBXO6 F-box protein 6 202307_s_at 0.8742 NM_000593 TAP1 transporter 1, ATP-binding cassette, sub-family B 204698_at 0.8735 NM_002201 ISG20 interferon stimulated gene 20 kDa 218986_s_at 0.8703 NM_017631 SGRA12061 Hypothetical protein FLJ20035 FLJ20035 205569_at 0.8675 NM_014398 LAMP3 lysosomal-associated membrane protein 3 223599_at 0.8664 NM_001003818 TRIMP1 tripartite motif-containing pseudogene 1 230866_at; 0.8656; NM_006639 CYSLTR1 cysteinyl leukotriene receptor 1 231747_at 0.8600 216565_x_at 0.8650 XM_497663 LOC391020 similar to Interferon-induced transmembrane protein 3 223952_x_at; 0.8623; NM_005771 DHRS9 dehydrogenase/reductase SDR 224009_x_at; 0.8535; family member 9 219799_s_at 0.8479 205241_at 0.8614 NM_001953 SCO2 SCO cytochrome oxidase deficient homolog 2 yeast 227458_at; 0.8601; NM_014143 PDL1/B7-H1 programmed cell death 1 ligand 1 223834_at 0.7465 209969_s_at 0.8576 NM_007315 STAT1 signal transducer and activator of transcription 1, 91 kDa 218999_at 0.8561 NM_018295 AGPR4538 hypothetical protein MGC5242 210705_s_at 0.8341 NM_033034 TRIM5 tripartite motif-containing 5 223167_s_at 0.8334 NM_013396 USP25 ubiquitin specific protease 25 229625_at; 0.8324; NM_004120 GBP5 guanylate binding protein 5 238581_at 0.8173 202837_at 0.8278 NM_006700 TRAFD1 TRAF-type zinc finger domain containing 1 223849_s_at 0.8180 NM_020963 MOV10 Mov10, Moloney leukemia virus 10, homolog mouse 222498_at; 0.8175; NM_022461 AZI2 5-azacytidine induced 2 227905_s_at 0.7115 217933_s_at 0.8138 NM_015907 LAP3 leucine aminopeptidase 3 219519_s_at; 0.8108; NM_023068 SIGLEC1 sialoadhesin 44673_at 0.7884 208392_x_at 0.8084 NM_004509 SP110 SP110 nuclear body protein 239988_at 0.8079 NM_017912 SKKS30637 Hect domain and RLD 6 230314_at 0.8074 P_ADH28842 CMLM110 chronic myclogenous leukaemia (CML) gene marker #110 227347_x_at 0.8047 NM_021170 HES4 hairy and enhancer of split 4 Drosophila 202411_at 0.8038 NM_005532 IFI27 interferon, alpha-inducible protein 27 205003_at 0.7974 NM_014705 DOCK4 dedicator of cytokinesis 4 212185_x_at; 0.7969; NM_005953 MT2A metallothionein 2A 206461_x_at; 0.7758; 217165_x_at 0.7168 235256_s_at; 0.7957; NM_138801 GALM galactose mutarotase aldose 1- 234974_at 0.7601 epimerase 206513_at 0.7891 NM_004833 AIM2 absent in melanoma 2 209546_s_at 0.7869 NM_003661 APOL1 apolipoprotein L, 1 204415_at 0.7838 NM_002038 G1P3 interferon, alpha-inducible protein clone IFI-6-16 206553_at 0.7821 NM_001032731 OAS2 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 226169_at 0.7746 NM_030962 SBF2 SET binding factor 2 244398_x_at; 0.7742; NM_152373 ZNF684 zinc finger protein 684 232563_at 0.7017 238439_at 0.7659 NM_144590 ANKRD22 ankyrin repeat domain 22 227649_s_at 0.7646 NM_015326 SRGAP2 SLIT-ROBO Rho GTPase activating protein 2 220998_s_at 0.7644 NM_030930 UNC93B1 unc-93 homolog B1 C. elegans 224973_at 0.7612 NM_017633 FAM46A family with sequence similarity 46, member A 232034_at 0.7581 LOC203274 231455_at 0.7560 NM_001001695 FLJ42418 FLJ42418 208581_x_at; 0.7546; NM_005952 MT1X metallothionein 1X 204326_x_at; 0.5699; 212859_x_at 0.5285 224225_s_at 0.7545 NM_016135 ETV7 ets variant gene 7 (TEL2 oncogene) 205875_s_at 0.7543 NM_016381 TREX1 three prime repair exonuclease 1 209286_at 0.7522 NM_006449 CDC42EP3 CDC42 effector protein Rho GTPase binding 3 205715_at 0.7472 NM_004334 BST1 bone marrow stromal cell antigen 1 212285_s_at 0.7414 NM_198576 AGRN agrin 230695_s_at 0.7381 NM_152732 C6orf206 chromosome 6 open reading frame 206 219364_at 0.7381 NM_024119 LGP2 likely ortholog of mouse D11lgp2 238455_at 0.7371 NM_032812 PLXDC2 Plexin domain containing 2 201641_at 0.7343 NM_004335 BST2 Bone marrow stromal antigen 2 219439_at 0.7273 NM_020156 C1GALT1 core 1 synthase, glyc-N- acetylgal 3-beta-galtransferase, 1 234942_s_at 0.7226 NM_052951 DNTTIP1 deoxynucleotidyltransferase, terminal, interacting protein 1 214933_at 0.7212 NM_000068 CAC1A calcium channel, voltage- dependent, P/Q type, alpha 1A 219055_at 0.7189 NM_018079 SRBD1 S1 RNA binding domain 1 225447_at 0.7179 NM_000408 GPD2 glycerol-3-phosphate dehydrogenase 2 mitochondrial 236285_at 0.7173 P_AAF17573 SYN22A2 Breast cancer associated SYN22A2 coding sequence 200923_at 0.7164 NM_005567 LGALS3BP lectin, galactoside-binding, soluble, 3 binding protein 220104_at 0.7159 NM_020119 ZC3HAV1 zinc finger CCCH-type, antiviral 1 216950_s_at; 0.7133; NM_000566 FCGR1A Fc fragment of IgG, high affinity 214511_x_at 0.7050 Ia, receptor CD64 230997_at 0.7109 NM_145755 TTC21A tetratricopeptide repeat domain 21A 210889_s_at 0.7099 NM_001002273 FCGR2B Low affinity immunoglobulin gamma fc receptor ii-b 211456_x_at 0.7045 NM_001039954 MT1P2 metallothionein 1 pseudogene 2 235456_at; 0.6926; NM_021063 HIST1H2BD histone 1, H2bd 235681_at 0.4913 229194_at; 0.6917; NM_032373 PCGF5 polycomb group ring finger 5 235331_x_at 0.6769 230333_at 0.6851 NM_002970 SAT Spermidine/spermine N1- acetyltransferase 231956_at 0.6813 NM_020954 KIAA1618 KIAA1618 235175_at 0.6803 NM_052941 GBP4 guanylate binding protein 4 232149_s_at 0.6777 NM_003580 NSMAF neutral sphingomyelinase N- SMase activation assoc factor 221653_x_at 0.6762 NM_030882 APOL2 apolipoprotein L, 2 219716_at 0.6689 NM_030641 APOL6 apolipoprotein L, 6 214909_s_at; 0.6669; NM_013974 DDAH2 dimethylarginine 215537_x_at 0.6366 dimethylaminohydrolase 2 207500_at 0.6654 NM_004347 CASP5 caspase 5, apoptosis-related cysteine protease 232081_at 0.6648 NM_004915 ABCG1 ATP-binding cassette, sub- family G WHITE, member 1 230166_at 0.6571 NM_133465 KIAA1958 KIAA1958 239143_x_at 0.6554 NM_016271 RNF138 ring finger protein 138 217823_s_at 0.6543 NM_016021 UBE2J1 ubiquitin-conjugating enzyme E2, J1 UBC6 homolog, yeast 242109_at 0.6501 NM_006519 TCTEL1 t-complex-associated-testis- expressed 1-like 1 206175_x_at 0.6420 NM_013360 ZNF230 zinc finger protein 230 220252_x_at 0.6318 NM_025159 CXorf21 chromosome X open reading frame 21 227268_at 0.6213 NM_016125 PLFL4625 PTD016 protein 216336_x_at 0.6153 NM_153341 IBRDC3 IBR domain containing 3 229804_x_at 0.6077 NM_018491 CBWD1 COBW domain containing 1 236013_at 0.6011 NM_000721 CAC1E calcium channel, voltage- dependent, alpha 1E subunit 227004_at 0.5968 NM_003159 CDKL5 cyclin-dependent kinase-like 5 226099_at 0.5788 NM_012081 ELL2 elongation factor, R polymerase II, 2 227947_at 0.5761 NM_014721 PHACTR2 phosphatase and actin regulator 2 233264_at 0.5515 AK022088 FLJ12026 HEMBB1001816 235348_at 0.5251 NM_032859 C13orf6 chromosome 13 open reading frame 6 225872_at 0.5053 NM_025181 SLC35F5 solute carrier family 35, member F5 207291_at 0.4851 NM_024081 PRRG4 proline rich Gla G- carboxyglutamic acid 4 transmembrane 234997_x_at 0.4617 CD684982 EST1502 human spermidine/spermine N1 acetyl transferase

Example 3

To further assess the extent to which gene combinations comprising one or more of the genes that have been identified herein correlate with an interferon response gene signature, the Pearson correlation of all possible three-gene combinations of 24 selected genes (Table 4A) were assessed. Data are shown in Table 4B.

Materials and Methods

PAXgene tubes from Qiagen/PreAnalytix (Valencia, Calif.) were used to collect whole blood from 35 SLE samples and 10 healthy donors. RNA was prepared by using a blood RNA isolation kit from Qiagen/PreAnalytix (Valencia, Calif.) and the expression of twenty-four interferon-alpha (IFN α) responsive genes was assayed using routine methods, e.g., by using primers/probes with TaqMan reagents from ABI (Foster City, Calif.). Relative abundance was determined by normalizing expression to RPL19. One “healthy” donor sample was removed from the analysis due to abnormally high expression of IFN responsive genes probably due to a recent viral infection. An Interferon Signature Metric (ISM) score was defined in the following manner:

-   -   1. The average expression for each gene was calculated in the         normal samples (“average normal expression”).     -   2. Ratio of expression relative to the average normal expression         (step #1) was tabulated.     -   3. The ISM score is defined for each sample using a set of         genes. The

ISM score was the average of the expression ratios (step #2) for the set of genes in the given sample.

From the 24 IFNα responsive genes, it was possible to generate 2024 unique three-gene subsets. For each of the possible 2024 three-gene combination, Pearson correlations between three-gene ISM score and the twenty four-gene ISM score were calculated. All numerical analysis was performed using R (http://www [insert period] r-project [insert period] org/).

Result and Analysis

While most healthy donor samples had an ISM score near one, a significant fraction of SLE patients had considerably higher ISM scores. Further, all three-gene combination ISM scores served as high quality surrogates for the twenty four-gene ISM score. The histogram for the three-gene ISM score correlation with the twenty four-gene ISM score is shown in FIG. 5. The lowest Pearson correlation was 0.73 and 70% of the correlations were greater than 0.95.

As evident from Table 4B, all combinations showed significant correlation values, with the lowest value being about 0.73. This demonstrated the usefulness and flexibility of the genes disclosed hereinabove as markers of disease. Most, but not all, of the 24 selected genes are from Tables 1, 2 and/or 3. The high correlation observed, even for combinations comprising a gene(s) that is not listed in Tables 1, 2 and/or 3, further confirmed the usefulness and broad applicability of the genes disclosed hereinabove as disease markers.

TABLE 4A List of selected 24 genes, with corresponding RefSeq ID. EPSTI1 NM_001002264 RIG1 NM_014314 (DDX58) OAS3 NM_006187 HERC5 NM_016323 PARP9 NM_031458 SAMD9L NM_152703 TYKI NM_207315 CHMP5 NM_016410 ZBP1 NM_030776 CIG5 NM_080657 (RSAD2) IFI44 NM_006417 IFI44L NM_006820 IFIT1 NM_001548 IFIT4 (IFIT3) NM_001549 IFIT5 NM_012420 IRF7 NM_004029 G1P2 NM_005101 MX1 NM_002462 OAS1 NM_002534 OAS2 NM_002535 OASL NM_003733 SP110 NM_004509 RIGE NM_002346 (LY6E) XIAP NM_001167

TABLE 4B All possible 3-gene combinations of a selected group of 24 genes, indicated with their respective Pearson correlation values. Pearson Gene1 Gene2 Gene3 Correlation IFIT4 OAS1 MX1 0.996514 OASL CHMP5 ZBP1 0.996478 IFI44L OASL CIG5 0.996391 IFI44L CIG5 ZBP1 0.995869 EPSTI1 TYKI MX1 0.995702 IFIT4 HERC5 TYKI 0.995611 IFIT4 TYKI XIAP 0.995609 IFI44L OASL ZBP1 0.995602 IFI44L IFIT4 OASL 0.995504 IFIT4 OAS1 IFIT1 0.995422 EPSTI1 HERC5 TYKI 0.995392 IFI44L EPSTI1 OASL 0.995385 IFI44L EPSTI1 OAS3 0.995345 EPSTI1 TYKI IFIT1 0.99515 G1P2 SAMD9L SP110 0.99489 IRF7 HERC5 TYKI 0.994867 IFIT5 CIG5 ZBP1 0.994863 IFI44L EPSTI1 ZBP1 0.994776 IFI44L SP110 ZBP1 0.994649 RIG1 IRF7 HERC5 0.994588 TYKI IFIT1 XIAP 0.994564 IFIT4 TYKI MX1 0.994522 OASL IFI44 ZBP1 0.994503 EPSTI1 G1P2 SAMD9L 0.994402 IRF7 SAMD9L MX1 0.99428 IFI44L OAS2 OASL 0.994232 IFI44L CIG5 SP110 0.994183 TYKI MX1 XIAP 0.994176 IFI44L OASL IRF7 0.994168 IFIT5 IFIT4 OAS3 0.994107 IRF7 HERC5 SAMD9L 0.994056 OASL CIG5 CHMP5 0.994043 IRF7 TYKI IFIT1 0.993998 TYKI IFIT1 SP110 0.993932 IFIT4 TYKI IFIT1 0.993875 CIG5 HERC5 TYKI 0.993865 IFIT5 IFIT4 ZBP1 0.993786 OAS2 OASL CHMP5 0.993676 IFI44L IFIT4 RIGE 0.993594 EPSTI1 OAS3 CHMP5 0.993546 IFI44L IFIT4 OAS3 0.993513 EPSTI1 G1P2 TYKI 0.993511 EPSTI1 G1P2 HERC5 0.99349 OAS1 IRF7 IFIT1 0.99348 IRF7 TYKI MX1 0.993472 IFIT5 OAS2 ZBP1 0.993459 IRF7 HERC5 IFIT1 0.99345 IFI44L OASL XIAP 0.993443 OAS1 CIG5 IFIT1 0.993431 IFIT4 IRF7 TYKI 0.993429 HERC5 TYKI SP110 0.993356 IFIT4 RIG1 TYKI 0.993297 OAS1 IRF7 MX1 0.993259 IFIT5 IRF7 ZBP1 0.993164 IFIT4 G1P2 OAS1 0.993068 G1P2 IRF7 HERC5 0.992975 IFI44L OAS2 CIG5 0.992931 CIG5 SAMD9L TYKI 0.992894 IRF7 HERC5 MX1 0.99289 OAS2 OASL IFI44 0.992876 HERC5 TYKI XIAP 0.992863 OASL CIG5 IFI44 0.992852 CIG5 IFI44 ZBP1 0.992827 IFIT5 OAS2 IRF7 0.992666 IFI44L IRF7 CIG5 0.992636 TYKI MX1 SP110 0.992558 IFI44L OASL MX1 0.992556 OAS1 CIG5 MX1 0.992546 EPSTI1 IFI44 OAS3 0.992546 G1P2 CIG5 SAMD9L 0.992522 EPSTI1 RIG1 TYKI 0.99252 OASL SAMD9L IFIT1 0.992509 IFIT5 EPSTI1 ZBP1 0.992466 IFI44L HERC5 RIGE 0.992413 CIG5 TYKI IFIT1 0.992392 IFI44L IRF7 ZBP1 0.992374 G1P2 IRF7 SAMD9L 0.992327 IFIT4 SAMD9L TYKI 0.992311 IFI44L OASL SP110 0.992307 IFIT5 OAS2 CIG5 0.992229 IFI44L IFIT1 RIGE 0.992209 IFI44L IFIT4 ZBP1 0.992195 IFI44L CIG5 XIAP 0.992193 IFIT5 EPSTI1 OAS3 0.99217 IFI44L OAS2 EPSTI1 0.992154 IFI44L EPSTI1 CIG5 0.992137 IFI44L OAS2 SP110 0.99207 EPSTI1 SAMD9L TYKI 0.99207 IFI44L MX1 RIGE 0.992058 OASL CHMP5 XIAP 0.992049 G1P2 HERC5 XIAP 0.992014 IFI44L OASL IFIT1 0.992005 G1P2 SAMD9L ZBP1 0.991994 IFI44L EPSTI1 RIGE 0.991991 IFIT5 OAS2 MX1 0.991941 IRF7 SAMD9L IFIT1 0.991891 IFI44L IRF7 OAS3 0.991715 IFIT4 EPSTI1 TYKI 0.991674 EPSTI1 G1P2 OAS1 0.991603 IFI44L OAS2 ZBP1 0.991594 EPSTI1 OAS1 MX1 0.991562 CIG5 HERC5 SAMD9L 0.99156 IFIT5 OAS3 IFIT1 0.991555 IFIT5 OASL MX1 0.991528 OAS1 IFIT1 MX1 0.991486 IFIT4 G1P2 SAMD9L 0.991439 IFIT5 CIG5 XIAP 0.991397 OAS2 IFI44 ZBP1 0.991331 EPSTI1 OASL CHMP5 0.991303 HERC5 IFIT1 XIAP 0.991268 G1P2 HERC5 SP110 0.99125 CIG5 TYKI MX1 0.991247 OASL SAMD9L MX1 0.991199 IFIT5 IFIT4 OAS2 0.991186 IFIT5 IRF7 OAS3 0.991178 IFI44L OAS2 IRF7 0.991172 IFIT5 IFIT4 OASL 0.991098 IFIT5 IRF7 CIG5 0.991095 IFI44L OASL HERC5 0.991094 IFI44L RIGE XIAP 0.99101 OASL IRF7 CHMP5 0.990968 IFIT4 SAMD9L MX1 0.990947 IFIT5 OAS3 MX1 0.990942 IFIT4 G1P2 HERC5 0.990937 G1P2 OAS1 CIG5 0.990933 G1P2 IFIT1 XIAP 0.990886 SAMD9L MX1 XIAP 0.990878 OAS3 CHMP5 SP110 0.990877 G1P2 TYKI SP110 0.990867 EPSTI1 OAS1 IFIT1 0.990838 G1P2 OASL SAMD9L 0.990826 IFI44L CIG5 RIGE 0.990812 SAMD9L TYKI SP110 0.990776 IFIT5 CIG5 MX1 0.990775 CHMP5 RIGE XIAP 0.990758 OASL TYKI IFIT1 0.990748 HERC5 MX1 XIAP 0.990729 EPSTI1 G1P2 IFIT1 0.9907 IRF7 OAS3 CHMP5 0.990687 EPSTI1 OASL IFI44 0.990632 G1P2 OAS1 IFIT1 0.990614 IFIT5 XIAP ZBP1 0.990611 IFIT4 OAS1 HERC5 0.990512 IFIT4 HERC5 SAMD9L 0.990506 EPSTI1 IFI44 ZBP1 0.990464 OASL CHMP5 SP110 0.990463 IFIT5 OASL IFIT1 0.990412 EPSTI1 TYKI XIAP 0.990325 EPSTI1 IRF7 TYKI 0.990315 G1P2 SAMD9L XIAP 0.990306 IFI44L CIG5 OAS3 0.990281 IFIT5 OAS2 EPSTI1 0.990115 CIG5 SAMD9L MX1 0.990079 SAMD9L TYKI ZBP1 0.989993 OAS2 TYKI IFIT1 0.989986 EPSTI1 SAMD9L MX1 0.989945 IFI44 RIGE ZBP1 0.989942 IFIT5 MX1 RIGE 0.989937 IFI44L OAS3 SP110 0.989929 IFIT5 MX1 ZBP1 0.98985 IFI44L SAMD9L RIGE 0.989814 CIG5 IFI44 RIGE 0.989794 OAS2 CIG5 IFI44 0.989763 OASL HERC5 SAMD9L 0.989717 IFIT4 IRF7 SAMD9L 0.989667 IFIT5 IFIT1 RIGE 0.989587 IFIT4 IRF7 HERC5 0.989574 IFIT5 OASL ZBP1 0.989563 TYKI IFIT1 ZBP1 0.989561 G1P2 CIG5 HERC5 0.989534 HERC5 TYKI MX1 0.9895 EPSTI1 IFI44 RIGE 0.989498 G1P2 OAS1 MX1 0.989491 IRF7 SAMD9L TYKI 0.989455 CIG5 IFI44 OAS3 0.989384 IFIT5 OASL CIG5 0.989345 IFIT4 G1P2 TYKI 0.989323 IFI44L OAS3 HERC5 0.989322 IFIT4 TYKI ZBP1 0.989292 IFIT5 SP110 ZBP1 0.98929 IFI44 SP110 ZBP1 0.989289 IFI44L XIAP ZBP1 0.989258 HERC5 TYKI IFIT1 0.989244 IFIT5 OAS2 IFIT1 0.989239 EPSTI1 G1P2 MX1 0.98921 G1P2 IRF7 IFIT1 0.989159 IFI44L IFIT4 OAS2 0.989146 OAS3 CHMP5 XIAP 0.989141 OASL OAS3 CHMP5 0.989136 OASL IFI44 XIAP 0.989112 IFI44L EPSTI1 SP110 0.989091 IFI44L IRF7 SP110 0.989077 IFI44L IFIT4 CIG5 0.989073 CIG5 OAS3 CHMP5 0.989057 IFI44 RIGE XIAP 0.989037 CIG5 SAMD9L IFIT1 0.989029 IFI44L CIG5 HERC5 0.989011 IFIT5 OAS3 HERC5 0.988963 IFIT4 HERC5 XIAP 0.988945 IFIT4 HERC5 MX1 0.988925 IFIT5 OAS3 XIAP 0.988891 IFI44L IFIT4 SP110 0.988869 IFI44L OAS3 XIAP 0.988845 CHMP5 RIGE ZBP1 0.988767 CIG5 CHMP5 RIGE 0.988756 IFI44L OAS3 IFIT1 0.988746 RIG1 IRF7 SAMD9L 0.988717 IFI44 MX1 RIGE 0.988705 SAMD9L IFIT1 XIAP 0.988634 EPSTI1 CHMP5 RIGE 0.988543 IFI44L CIG5 MX1 0.988509 IFIT5 MX1 SP110 0.988438 HERC5 TYKI ZBP1 0.988437 OAS1 IFIT1 ZBP1 0.988433 IFIT4 HERC5 IFIT1 0.988422 IRF7 TYKI XIAP 0.988382 IFIT5 IFIT1 ZBP1 0.988359 IFIT5 OAS2 OASL 0.988341 IFIT5 IFIT4 CIG5 0.988316 SAMD9L IFIT1 ZBP1 0.988312 G1P2 IFIT1 SP110 0.988303 OAS1 IFIT1 XIAP 0.9883 OASL SAMD9L TYKI 0.988278 HERC5 CHMP5 RIGE 0.988269 IFIT4 OAS1 TYKI 0.988268 OAS2 OAS1 IFIT1 0.988248 G1P2 MX1 XIAP 0.988232 OAS1 HERC5 MX1 0.988215 OAS1 CIG5 HERC5 0.988211 HERC5 SAMD9L ZBP1 0.988167 OAS2 HERC5 TYKI 0.988163 IFI44 OAS3 ZBP1 0.988139 CIG5 CHMP5 ZBP1 0.988136 IFI44L IRF7 RIGE 0.988106 IFIT4 IFI44 OAS3 0.988101 OAS2 SAMD9L TYKI 0.988081 IFIT5 CIG5 IFIT1 0.988073 IFIT5 EPSTI1 CIG5 0.988072 IFIT4 OASL IFI44 0.98801 IFI44 HERC5 RIGE 0.987984 IFIT4 G1P2 XIAP 0.987951 IFI44L MX1 SP110 0.98795 OAS1 MX1 XIAP 0.987945 RIG1 IRF7 IFIT1 0.987936 IFIT4 RIG1 HERC5 0.987933 IFIT4 SAMD9L IFIT1 0.987928 IFI44L EPSTI1 IRF7 0.987927 IFIT4 OAS1 IRF7 0.987914 IFIT5 OASL XIAP 0.987913 IFIT4 IFI44 RIGE 0.987912 IFIT5 CIG5 OAS3 0.987904 IFIT4 SAMD9L XIAP 0.987896 OAS2 G1P2 SAMD9L 0.987775 OASL HERC5 IFIT1 0.987735 IRF7 IFI44 OAS3 0.987734 IFIT5 CIG5 HERC5 0.98773 EPSTI1 HERC5 MX1 0.987723 G1P2 CIG5 TYKI 0.98772 IFIT5 IFIT4 RIGE 0.987715 IFI44L RIGE ZBP1 0.987715 IFIT5 OASL IRF7 0.987699 OAS1 HERC5 IFIT1 0.987696 EPSTI1 HERC5 SAMD9L 0.987685 OASL IRF7 IFI44 0.98768 IFI44L RIG1 OASL 0.987635 EPSTI1 RIG1 G1P2 0.987607 IFIT4 CIG5 TYKI 0.987605 OAS2 EPSTI1 IFI44 0.987589 IFIT5 OAS2 XIAP 0.987588 OAS2 TYKI MX1 0.987555 OASL IFI44 MX1 0.987554 CHMP5 MX1 RIGE 0.987534 IFI44L OAS3 MX1 0.987521 IFI44 OAS3 SP110 0.987441 EPSTI1 HERC5 IFIT1 0.987435 G1P2 HERC5 IFIT1 0.987431 IFIT4 TYKI SP110 0.9874 OAS2 IFI44 RIGE 0.987335 IRF7 HERC5 XIAP 0.987327 OAS3 CHMP5 ZBP1 0.987314 HERC5 SAMD9L XIAP 0.987305 G1P2 HERC5 SAMD9L 0.987303 OASL HERC5 TYKI 0.987292 RIG1 IRF7 TYKI 0.987272 IFI44 OAS3 XIAP 0.987263 OASL TYKI MX1 0.987226 SAMD9L MX1 ZBP1 0.987216 G1P2 TYKI XIAP 0.987186 RIG1 IFIT1 XIAP 0.987143 CIG5 HERC5 IFIT1 0.987143 OASL CHMP5 MX1 0.987113 IFIT5 CIG5 SP110 0.987103 HERC5 SAMD9L MX1 0.987078 EPSTI1 SAMD9L IFIT1 0.987021 IFI44L EPSTI1 XIAP 0.986996 IFIT4 G1P2 IFIT1 0.986962 IFIT5 OAS2 SP110 0.986961 TYKI IFIT1 MX1 0.986955 IFI44 IFIT1 RIGE 0.98694 G1P2 OAS1 IRF7 0.986929 RIG1 TYKI XIAP 0.986927 IFI44L SP110 XIAP 0.986913 IFIT5 EPSTI1 OASL 0.986895 OASL IFI44 SP110 0.986847 SAMD9L MX1 SP110 0.986839 IFIT4 IFIT1 XIAP 0.986801 G1P2 SAMD9L MX1 0.986792 SAMD9L TYKI MX1 0.986776 IFIT1 MX1 XIAP 0.986772 RIG1 HERC5 XIAP 0.986653 IFIT4 SAMD9L ZBP1 0.986638 CIG5 IFI44 SP110 0.986615 RIG1 TYKI MX1 0.986584 IFI44L CIG5 IFIT1 0.986574 CIG5 TYKI XIAP 0.986567 SAMD9L TYKI XIAP 0.986554 IFI44L RIG1 RIGE 0.986514 IFIT4 OASL CHMP5 0.986483 IFI44L OAS2 MX1 0.986478 CIG5 IFI44 XIAP 0.98647 IFI44L G1P2 RIGE 0.986469 IRF7 IFI44 ZBP1 0.986437 EPSTI1 CIG5 IFI44 0.986418 RIG1 CIG5 TYKI 0.986387 RIG1 TYKI IFIT1 0.986336 IFIT5 EPSTI1 MX1 0.986313 IRF7 IFIT1 XIAP 0.986307 IFIT4 MX1 XIAP 0.98627 IFIT4 OAS3 CHMP5 0.986258 G1P2 IRF7 MX1 0.986258 OAS2 IFI44 SP110 0.986255 IFIT5 G1P2 CIG5 0.986247 IFI44L HERC5 SP110 0.986229 G1P2 OASL IFIT1 0.986183 G1P2 SAMD9L IFIT1 0.986168 TYKI MX1 ZBP1 0.986151 CHMP5 IFIT1 RIGE 0.986136 OAS1 IRF7 HERC5 0.986057 IRF7 IFIT1 MX1 0.986039 IFIT5 HERC5 RIGE 0.985983 IFIT5 OAS2 HERC5 0.985946 RIG1 IRF7 MX1 0.985944 IFI44 XIAP ZBP1 0.985944 IFI44L G1P2 OASL 0.985941 IFIT5 OASL HERC5 0.98592 G1P2 HERC5 MX1 0.985913 OAS2 OAS1 MX1 0.98591 IFIT5 G1P2 ZBP1 0.985875 OAS1 CIG5 TYKI 0.985852 RIG1 G1P2 HERC5 0.985831 OAS1 OASL IFIT1 0.985827 G1P2 CIG5 IFIT1 0.985799 IFI44L OAS3 ZBP1 0.985763 IFI44L OAS2 XIAP 0.985746 IFIT5 HERC5 ZBP1 0.985738 RIG1 HERC5 MX1 0.985734 IRF7 CIG5 TYKI 0.985724 CIG5 HERC5 MX1 0.985709 IFIT4 RIG1 SAMD9L 0.985702 OAS2 SAMD9L MX1 0.985696 OAS3 HERC5 CHMP5 0.985677 OASL HERC5 CHMP5 0.985675 EPSTI1 G1P2 XIAP 0.985614 IFIT4 G1P2 MX1 0.985575 OAS2 SAMD9L IFIT1 0.985558 IFI44 OAS3 HERC5 0.985493 IFIT4 OASL TYKI 0.985491 IFIT5 OAS2 G1P2 0.985467 CHMP5 SP110 ZBP1 0.985431 RIG1 MX1 XIAP 0.985418 IFI44L HERC5 ZBP1 0.985411 G1P2 HERC5 ZBP1 0.985399 IFI44L MX1 ZBP1 0.985399 RIG1 HERC5 IFIT1 0.985388 OASL IFI44 IFIT1 0.985349 RIG1 OAS1 MX1 0.985314 IFIT4 IFI44 ZBP1 0.985306 IFIT4 OASL SAMD9L 0.985271 OASL IFI44 HERC5 0.985262 IFIT4 OAS2 TYKI 0.985259 IRF7 CHMP5 RIGE 0.985241 G1P2 IRF7 TYKI 0.98524 RIG1 SAMD9L MX1 0.985203 G1P2 OASL HERC5 0.985184 IFI44L IFIT4 EPSTI1 0.985167 SAMD9L IFIT1 SP110 0.985161 HERC5 SAMD9L SP110 0.985136 IFI44L EPSTI1 MX1 0.985133 IFIT4 CHMP5 RIGE 0.985089 IFI44L IFIT1 SP110 0.985074 OASL CHMP5 IFIT1 0.985052 IFI44L OAS2 RIGE 0.985038 OAS1 MX1 ZBP1 0.985036 IFIT5 G1P2 SP110 0.985035 RIG1 HERC5 TYKI 0.98502 IFI44L OAS2 HERC5 0.985013 OASL IFI44 OAS3 0.984994 IFIT5 OAS3 ZBP1 0.984992 IRF7 CIG5 IFI44 0.984947 EPSTI1 CHMP5 ZBP1 0.984947 IFI44L G1P2 SP110 0.984929 IFIT5 IFIT4 SP110 0.984889 IFI44 OAS3 MX1 0.984882 IFIT5 IFIT4 XIAP 0.984858 G1P2 OAS1 ZBP1 0.984857 IFI44L OAS2 IFIT1 0.984833 IFIT5 EPSTI1 IRF7 0.984785 IFI44L IFIT1 ZBP1 0.984771 G1P2 OAS1 HERC5 0.984751 IFI44L OAS3 SAMD9L 0.984637 IFIT5 EPSTI1 XIAP 0.984622 OAS2 IRF7 IFI44 0.984619 IFIT4 IRF7 IFIT1 0.984565 IFIT5 IFIT1 SP110 0.984547 SAMD9L TYKI IFIT1 0.984535 HERC5 SAMD9L IFIT1 0.984528 IFI44L CIG5 TYKI 0.984518 RIG1 OAS1 IFIT1 0.984505 IFI44L OASL SAMD9L 0.984455 IRF7 IFI44 RIGE 0.984421 IFI44L G1P2 CIG5 0.98441 OAS2 CHMP5 RIGE 0.98438 G1P2 TYKI IFIT1 0.984362 IFIT5 G1P2 OASL 0.98435 SAMD9L CHMP5 RIGE 0.98435 IFIT4 OAS1 CIG5 0.984347 OAS2 HERC5 SAMD9L 0.98434 IFIT4 G1P2 IRF7 0.984323 G1P2 HERC5 TYKI 0.984302 IRF7 CIG5 SAMD9L 0.984261 EPSTI1 G1P2 IRF7 0.984258 OAS1 TYKI MX1 0.984212 IFI44L RIG1 CIG5 0.984189 IFI44 OAS3 IFIT1 0.984148 OAS1 CIG5 SAMD9L 0.984088 IRF7 SAMD9L XIAP 0.984046 IFIT4 OAS1 XIAP 0.983986 G1P2 MX1 SP110 0.983965 OAS1 TYKI IFIT1 0.983952 IFIT4 OAS1 SAMD9L 0.983939 IRF7 MX1 XIAP 0.983917 G1P2 IFI44 RIGE 0.983911 EPSTI1 OAS1 TYKI 0.983904 IFI44L OASL TYKI 0.983891 IFIT5 OAS2 PARP9 0.983888 RIG1 G1P2 XIAP 0.983881 IFIT5 G1P2 RIGE 0.983874 OAS2 CHMP5 ZBP1 0.983861 IFIT4 RIG1 OAS1 0.983828 G1P2 IFIT1 ZBP1 0.983828 IFIT4 IRF7 MX1 0.983803 OASL HERC5 MX1 0.983775 RIG1 CIG5 SAMD9L 0.983728 IFIT5 RIGE XIAP 0.983696 HERC5 IFIT1 SP110 0.983625 IFIT5 CIG5 PARP9 0.983607 OASL CHMP5 RIGE 0.983598 IFI44L IFIT4 XIAP 0.983588 IRF7 SAMD9L ZBP1 0.983584 IFIT5 OAS3 SAMD9L 0.983578 G1P2 TYKI ZBP1 0.983567 EPSTI1 OAS1 HERC5 0.983564 HERC5 IFIT1 MX1 0.983432 IFIT4 EPSTI1 G1P2 0.98341 IFIT5 MX1 XIAP 0.983401 SAMD9L IFIT1 MX1 0.983359 OAS3 CHMP5 MX1 0.983261 OAS2 IFI44 OAS3 0.983253 IFIT4 OAS1 ZBP1 0.983249 G1P2 IRF7 XIAP 0.983205 OAS3 CHMP5 IFIT1 0.983177 HERC5 IFIT1 ZBP1 0.983163 IFIT5 IFIT4 EPSTI1 0.983135 IFIT5 OAS3 SP110 0.983121 OAS1 IFIT1 SP110 0.983118 OAS2 CIG5 CHMP5 0.983111 IFI44L OASL OAS3 0.983103 G1P2 OAS1 SP110 0.983094 G1P2 OAS1 XIAP 0.983073 EPSTI1 IRF7 HERC5 0.983059 IFIT5 EPSTI1 G1P2 0.983057 IFIT5 IFIT4 IRF7 0.983047 IFI44L EPSTI1 HERC5 0.982974 OAS2 G1P2 OAS1 0.982973 IFIT4 RIG1 G1P2 0.98284 EPSTI1 IRF7 SAMD9L 0.982832 OAS3 SAMD9L IFIT1 0.98283 G1P2 TYKI MX1 0.982823 IFIT5 IRF7 MX1 0.982823 CIG5 IFI44 MX1 0.982815 IFIT5 IRF7 SP110 0.982806 EPSTI1 IFIT1 MX1 0.982804 OAS2 G1P2 HERC5 0.982779 HERC5 SAMD9L TYKI 0.982773 OASL TYKI CHMP5 0.98276 OAS1 SAMD9L MX1 0.982709 IFI44L TYKI RIGE 0.982691 IFI44L RIG1 OAS3 0.982688 IFIT4 IFIT1 MX1 0.982616 EPSTI1 CIG5 TYKI 0.982605 G1P2 CIG5 MX1 0.982585 TYKI CHMP5 RIGE 0.982585 IFI44L IFIT4 IRF7 0.982564 IFIT5 CIG5 TYKI 0.982489 G1P2 CHMP5 RIGE 0.98248 IFIT5 OAS3 PARP9 0.982456 IFIT4 EPSTI1 OAS1 0.98245 CIG5 CHMP5 XIAP 0.982444 IRF7 CHMP5 ZBP1 0.982443 IFIT5 SAMD9L RIGE 0.982442 CIG5 CHMP5 SP110 0.982432 IFIT5 EPSTI1 IFIT1 0.982364 IFIT5 G1P2 OAS3 0.982346 OAS2 IFI44 XIAP 0.982312 CIG5 IFI44 HERC5 0.982284 OAS2 G1P2 TYKI 0.982279 RIG1 G1P2 IFIT1 0.982209 IFI44L EPSTI1 G1P2 0.982198 OASL IFIT1 MX1 0.982165 OAS1 OASL MX1 0.982158 IFIT4 RIG1 MX1 0.982123 IFI44L TYKI SP110 0.982105 IFIT5 RIG1 ZBP1 0.982033 IFI44L SP110 RIGE 0.982032 IFI44L EPSTI1 IFIT1 0.982017 IFIT4 CIG5 SAMD9L 0.981999 IFIT5 IFIT4 MX1 0.981994 IFIT5 RIG1 OAS3 0.981987 OAS2 IFI44 MX1 0.981967 OAS2 G1P2 IFIT1 0.981944 IFIT4 OAS2 IFI44 0.981942 IFIT5 CIG5 RIGE 0.981929 RIG1 G1P2 SAMD9L 0.981924 EPSTI1 TYKI ZBP1 0.981909 IFIT5 RIG1 CIG5 0.9819 IFI44L G1P2 ZBP1 0.981887 OAS2 HERC5 IFIT1 0.981886 G1P2 OASL IFI44 0.981878 IFI44 SAMD9L RIGE 0.981874 IFIT5 SP110 XIAP 0.981729 CIG5 PARP9 SAMD9L 0.981712 OAS3 HERC5 SAMD9L 0.981703 EPSTI1 RIG1 HERC5 0.981663 IFIT5 EPSTI1 RIGE 0.981653 RIG1 SAMD9L ZBP1 0.981639 HERC5 MX1 SP110 0.981627 IFIT5 IRF7 XIAP 0.981625 IFIT4 RIG1 IFIT1 0.981605 IFI44 MX1 ZBP1 0.9816 RIG1 G1P2 IRF7 0.98159 IFI44L CIG5 PARP9 0.981588 IRF7 TYKI ZBP1 0.981572 IFI44L OAS1 CIG5 0.981535 OAS1 MX1 SP110 0.981522 IRF7 CIG5 HERC5 0.981504 OASL IFI44 RIGE 0.98145 IFIT5 HERC5 SP110 0.981389 IFIT4 CIG5 IFI44 0.981344 EPSTI1 PARP9 TYKI 0.981338 IFI44L IRF7 XIAP 0.981327 G1P2 IFIT1 MX1 0.981177 SAMD9L IFIT1 RIGE 0.981164 CHMP5 XIAP ZBP1 0.981034 IRF7 CIG5 CHMP5 0.98102 IFI44L CIG5 SAMD9L 0.980991 G1P2 OASL TYKI 0.980952 IFIT4 EPSTI1 SAMD9L 0.980931 CIG5 SAMD9L XIAP 0.98087 IFI44L RIG1 ZBP1 0.980847 G1P2 OASL CHMP5 0.98084 RIG1 CIG5 HERC5 0.980836 IFI44L OAS2 G1P2 0.980731 IFI44L OAS2 TYKI 0.980703 IFIT5 OAS2 RIG1 0.980656 IFI44L EPSTI1 TYKI 0.980647 RIG1 TYKI SP110 0.980579 EPSTI1 IFIT1 XIAP 0.980575 IFI44 SP110 RIGE 0.980565 IFI44 HERC5 ZBP1 0.980564 EPSTI1 CIG5 CHMP5 0.980544 EPSTI1 IFI44 XIAP 0.980516 IFIT5 OAS2 TYKI 0.980487 EPSTI1 IRF7 IFIT1 0.980474 IFI44L TYKI ZBP1 0.98047 IFI44L OAS2 OAS3 0.980469 EPSTI1 IFI44 SP110 0.980453 OAS1 OAS3 IFIT1 0.980399 G1P2 OASL MX1 0.980398 OAS1 CHMP5 RIGE 0.980281 IFIT5 EPSTI1 HERC5 0.98028 OAS1 SAMD9L IFIT1 0.980165 OAS3 TYKI CHMP5 0.980145 IFIT4 EPSTI1 HERC5 0.980116 OAS2 EPSTI1 CHMP5 0.980093 IFI44L OAS3 TYKI 0.980031 EPSTI1 HERC5 XIAP 0.980031 RIG1 SAMD9L IFIT1 0.98002 IFI44L OAS1 RIGE 0.980003 G1P2 SAMD9L RIGE 0.979981 IFIT5 IFIT1 XIAP 0.979977 IFI44L OASL PARP9 0.979964 CHMP5 SP110 RIGE 0.979922 OAS2 OAS3 CHMP5 0.979909 IFIT5 EPSTI1 SP110 0.97989 RIG1 HERC5 SAMD9L 0.97989 OAS2 CHMP5 SP110 0.979884 G1P2 SAMD9L TYKI 0.979881 IFIT5 OAS2 OAS3 0.979865 CIG5 IFIT1 MX1 0.97981 IFI44L G1P2 OAS3 0.979733 IFIT5 TYKI ZBP1 0.97972 CIG5 IFI44 IFIT1 0.979594 OAS2 IFI44 HERC5 0.979577 IFIT4 PARP9 TYKI 0.979539 OAS1 OAS3 CHMP5 0.979509 IFIT5 IRF7 RIGE 0.979509 TYKI XIAP ZBP1 0.979497 EPSTI1 MX1 XIAP 0.979484 CIG5 HERC5 XIAP 0.979467 IFIT5 RIGE ZBP1 0.979447 OAS3 SAMD9L CHMP5 0.979429 IFIT5 IRF7 IFIT1 0.979416 EPSTI1 IRF7 IFI44 0.979334 G1P2 CIG5 IFI44 0.979329 IFIT4 G1P2 ZBP1 0.979297 IFIT4 OASL IFIT1 0.979261 EPSTI1 IRF7 MX1 0.979237 IFI44 IFIT1 ZBP1 0.979214 IFI44L MX1 XIAP 0.979195 HERC5 MX1 ZBP1 0.979186 IFI44L IRF7 MX1 0.979186 OAS1 PARP9 IFIT1 0.979168 OAS2 IRF7 TYKI 0.979158 EPSTI1 RIG1 IFIT1 0.979136 EPSTI1 RIG1 MX1 0.979132 IFI44L OAS3 PARP9 0.979131 IFI44 MX1 SP110 0.979127 OAS1 IRF7 CIG5 0.979073 IFIT4 PARP9 SAMD9L 0.979062 IFIT4 HERC5 ZBP1 0.979058 RIG1 CHMP5 RIGE 0.979057 G1P2 CIG5 XIAP 0.979049 OAS1 HERC5 ZBP1 0.979026 IFI44L OASL RIGE 0.979004 OAS2 IRF7 CHMP5 0.978997 EPSTI1 RIG1 SAMD9L 0.978996 OASL IRF7 SAMD9L 0.978946 OAS2 HERC5 MX1 0.978889 HERC5 SAMD9L RIGE 0.978849 IFIT4 CIG5 HERC5 0.978822 IFIT4 OASL HERC5 0.978804 RIG1 G1P2 MX1 0.978789 IFIT5 CIG5 SAMD9L 0.978769 IFI44L OAS1 OAS3 0.978759 OAS3 SAMD9L MX1 0.978718 RIG1 TYKI ZBP1 0.978668 G1P2 IFI44 ZBP1 0.978638 EPSTI1 IFI44 MX1 0.97863 OAS2 IFI44 IFIT1 0.978619 CIG5 PARP9 TYKI 0.978512 EPSTI1 PARP9 SAMD9L 0.978467 EPSTI1 SAMD9L XIAP 0.978424 IFIT5 OAS3 TYKI 0.978409 IFIT5 OASL SP110 0.978403 IFI44 SP110 XIAP 0.978398 IFI44L IFIT4 MX1 0.978348 IFI44L OAS2 RIG1 0.978343 CIG5 IFIT1 XIAP 0.978337 RIG1 OASL CHMP5 0.978325 IFI44L SAMD9L ZBP1 0.978297 IFIT5 IFIT4 IFIT1 0.978296 OAS1 IRF7 TYKI 0.97822 IFIT5 OASL SAMD9L 0.978202 IRF7 TYKI SP110 0.978191 SAMD9L MX1 RIGE 0.978177 IFIT5 OASL TYKI 0.978163 PARP9 SAMD9L XIAP 0.978139 G1P2 IFI44 OAS3 0.978119 OAS1 HERC5 XIAP 0.97802 IFIT4 OAS2 SAMD9L 0.978019 IFI44L IRF7 HERC5 0.978014 RIG1 OASL SAMD9L 0.97801 G1P2 MX1 ZBP1 0.977958 IFI44L OAS2 PARP9 0.977945 OAS3 SAMD9L TYKI 0.977935 PARP9 IFIT1 XIAP 0.977901 G1P2 OAS1 OASL 0.977848 IFIT4 OAS2 OAS1 0.977813 IFI44 OAS3 SAMD9L 0.977801 IFI44 TYKI RIGE 0.97779 IFIT5 SAMD9L ZBP1 0.977734 OAS2 EPSTI1 TYKI 0.977724 PARP9 SAMD9L IFIT1 0.977718 RIG1 SAMD9L XIAP 0.977704 OAS3 TYKI IFIT1 0.977699 IFIT5 RIG1 OASL 0.977613 TYKI SP110 XIAP 0.977603 PARP9 TYKI IFIT1 0.977602 G1P2 OAS1 SAMD9L 0.977585 PARP9 TYKI XIAP 0.977542 OASL IFI44 TYKI 0.977504 IFIT5 IRF7 HERC5 0.977473 IRF7 IFI44 SP110 0.977459 IFIT5 EPSTI1 TYKI 0.977454 IRF7 CIG5 IFIT1 0.977446 OAS2 OAS1 HERC5 0.977433 CIG5 TYKI CHMP5 0.977361 IFIT5 IFIT4 HERC5 0.977353 IFIT4 EPSTI1 MX1 0.977281 IFI44L RIG1 SP110 0.977267 IFIT5 OASL PARP9 0.977265 IFIT4 EPSTI1 IFIT1 0.977256 RIG1 IFIT1 MX1 0.977255 IFI44L IFIT4 HERC5 0.977207 IFIT4 G1P2 CIG5 0.977176 CIG5 IFI44 TYKI 0.9771 OAS1 TYKI ZBP1 0.977098 OAS2 G1P2 IFI44 0.977092 OASL SAMD9L CHMP5 0.977068 IFIT4 IFI44 SP110 0.977067 G1P2 PARP9 SAMD9L 0.977067 IFIT4 CHMP5 ZBP1 0.977042 CIG5 HERC5 CHMP5 0.976966 IFIT4 G1P2 OASL 0.976916 OAS2 G1P2 MX1 0.976841 G1P2 IRF7 CIG5 0.97684 IFIT4 OAS1 PARP9 0.976808 OAS1 SAMD9L ZBP1 0.976794 IFIT4 OAS3 SAMD9L 0.976791 IFI44L IFIT1 XIAP 0.97677 IFI44L IRF7 IFIT1 0.976769 IFIT4 IFIT1 ZBP1 0.976725 G1P2 IFI44 SP110 0.976722 OAS2 OAS1 TYKI 0.976711 IFIT5 OAS2 RIGE 0.976711 EPSTI1 G1P2 PARP9 0.97671 IFIT5 TYKI SP110 0.976687 G1P2 OAS3 SAMD9L 0.976675 RIG1 IFI44 RIGE 0.976614 IFIT4 EPSTI1 IFI44 0.976597 RIG1 OAS3 CHMP5 0.976452 EPSTI1 OAS1 SAMD9L 0.976439 RIG1 G1P2 CIG5 0.976418 CIG5 CHMP5 MX1 0.976409 OAS1 IRF7 SAMD9L 0.976378 OAS3 HERC5 IFIT1 0.976367 OAS2 IRF7 SAMD9L 0.976358 IFIT5 IFIT4 G1P2 0.976294 EPSTI1 OAS1 IRF7 0.976291 IFI44 HERC5 SP110 0.976272 IFI44 OAS3 RIGE 0.976262 IFIT4 G1P2 SP110 0.976253 EPSTI1 G1P2 IFI44 0.976186 OASL IFIT1 XIAP 0.976181 IRF7 PARP9 SAMD9L 0.976177 IRF7 HERC5 ZBP1 0.976154 OAS3 CHMP5 RIGE 0.976111 OASL TYKI XIAP 0.976092 IFI44L OAS2 SAMD9L 0.976088 IFI44L OAS1 OASL 0.976054 IFIT1 MX1 SP110 0.976025 IFI44L HERC5 XIAP 0.975972 IFIT5 G1P2 XIAP 0.975971 IFIT5 OAS2 SAMD9L 0.975959 IFIT5 HERC5 XIAP 0.975949 OASL IFI44 SAMD9L 0.975842 IFIT5 EPSTI1 PARP9 0.975824 EPSTI1 IFI44 HERC5 0.975738 SAMD9L TYKI RIGE 0.975714 IFI44 OAS3 TYKI 0.975702 IFIT5 TYKI RIGE 0.97567 RIG1 CIG5 IFIT1 0.975658 HERC5 PARP9 SAMD9L 0.975637 G1P2 OAS3 CHMP5 0.975579 OAS1 HERC5 TYKI 0.975575 IFIT5 OASL OAS3 0.975559 IFI44L IFIT4 IFIT1 0.975549 SAMD9L XIAP ZBP1 0.975489 EPSTI1 OASL TYKI 0.975407 IFI44L EPSTI1 PARP9 0.975398 OASL IRF7 IFIT1 0.975396 RIG1 OAS1 CIG5 0.975346 RIG1 OASL IFIT1 0.975344 IFIT4 OAS1 OASL 0.975331 OAS3 HERC5 TYKI 0.975303 OAS1 IFI44 RIGE 0.975295 OAS2 IFIT1 MX1 0.97529 IFIT1 MX1 ZBP1 0.975252 CIG5 MX1 XIAP 0.975204 OAS1 CIG5 PARP9 0.97518 IFIT5 PARP9 ZBP1 0.975163 IFI44L OAS1 ZBP1 0.97516 IFI44L EPSTI1 RIG1 0.975122 IFIT4 OASL MX1 0.975118 OASL IRF7 TYKI 0.975116 OAS2 RIG1 TYKI 0.97509 OAS2 CHMP5 XIAP 0.975079 OASL SAMD9L XIAP 0.975079 HERC5 PARP9 IFIT1 0.975059 RIG1 G1P2 OAS1 0.975034 RIG1 OASL IFI44 0.974999 IFI44 OAS3 PARP9 0.974929 IFIT4 IFI44 XIAP 0.974925 IRF7 IFIT1 ZBP1 0.974912 PARP9 SAMD9L MX1 0.97489 OAS1 IFIT1 RIGE 0.974859 EPSTI1 SAMD9L ZBP1 0.974825 HERC5 PARP9 XIAP 0.974823 EPSTI1 TYKI SP110 0.974822 IFIT4 CIG5 IFIT1 0.974778 G1P2 OAS1 TYKI 0.974713 IFI44 IFIT1 SP110 0.974708 HERC5 PARP9 TYKI 0.9747 EPSTI1 G1P2 ZBP1 0.974674 IFI44L OAS2 OAS1 0.974667 IFI44 TYKI ZBP1 0.974642 EPSTI1 CHMP5 XIAP 0.974537 IFIT4 SAMD9L SP110 0.974501 TYKI CHMP5 ZBP1 0.974475 EPSTI1 G1P2 CIG5 0.974468 OAS1 IFI44 OAS3 0.974458 EPSTI1 IFI44 IFIT1 0.974387 OAS1 OAS3 MX1 0.974382 OAS2 TYKI XIAP 0.974363 OAS1 OASL HERC5 0.974357 IFIT5 G1P2 IRF7 0.974308 OAS1 OASL CHMP5 0.974297 TYKI IFIT1 RIGE 0.974282 OAS1 PARP9 MX1 0.974256 OAS2 IFI44 TYKI 0.974177 OAS1 CIG5 IFI44 0.974175 RIG1 IFI44 OAS3 0.974125 IFI44L IFIT4 TYKI 0.974105 OAS1 CIG5 CHMP5 0.974105 OAS2 PARP9 SAMD9L 0.974104 IRF7 CIG5 MX1 0.974084 CHMP5 SP110 XIAP 0.974042 EPSTI1 CHMP5 SP110 0.973988 OAS1 TYKI XIAP 0.973951 HERC5 CHMP5 ZBP1 0.973937 CIG5 TYKI ZBP1 0.973936 IFI44L SAMD9L SP110 0.973933 IFIT4 HERC5 PARP9 0.973933 IFIT5 OAS1 CIG5 0.97391 G1P2 PARP9 XIAP 0.973887 OAS1 CIG5 XIAP 0.973886 CHMP5 MX1 ZBP1 0.973864 TYKI CHMP5 SP110 0.973768 EPSTI1 PARP9 IFIT1 0.97373 IRF7 CHMP5 SP110 0.973693 CIG5 IFI44 PARP9 0.973655 G1P2 PARP9 IFIT1 0.973599 EPSTI1 CIG5 SAMD9L 0.973586 G1P2 IRF7 ZBP1 0.97357 EPSTI1 IRF7 CHMP5 0.973555 OASL IFI44 PARP9 0.973554 OAS2 TYKI CHMP5 0.973542 RIG1 G1P2 TYKI 0.973532 IRF7 IFI44 XIAP 0.973462 IFIT5 RIG1 RIGE 0.973451 IFIT5 IFIT4 TYKI 0.973442 G1P2 HERC5 PARP9 0.97344 OAS2 CHMP5 MX1 0.973422 PARP9 SAMD9L TYKI 0.973386 IFI44 MX1 XIAP 0.973355 RIG1 SAMD9L TYKI 0.973328 CIG5 CHMP5 IFIT1 0.973246 CIG5 HERC5 PARP9 0.973244 IFI44L IFIT4 G1P2 0.973197 OASL IRF7 HERC5 0.973112 IFIT4 CIG5 CHMP5 0.973104 OAS2 OAS1 SAMD9L 0.973103 G1P2 CIG5 CHMP5 0.973073 RIG1 G1P2 SP110 0.973048 IFIT4 CIG5 MX1 0.973006 IFI44L EPSTI1 OAS1 0.973006 IFIT4 OAS3 TYKI 0.973003 G1P2 XIAP ZBP1 0.97295 OASL PARP9 SAMD9L 0.972938 EPSTI1 HERC5 PARP9 0.972841 IFIT1 XIAP ZBP1 0.972814 IFIT4 PARP9 IFIT1 0.972796 CHMP5 MX1 SP110 0.972719 PARP9 TYKI MX1 0.972707 IFIT4 MX1 ZBP1 0.972638 IFI44L EPSTI1 SAMD9L 0.972539 IFIT5 IFIT1 MX1 0.972533 IFI44L G1P2 XIAP 0.972515 EPSTI1 IFI44 TYKI 0.972495 IFIT4 OAS2 HERC5 0.97249 IFIT4 RIG1 XIAP 0.97246 IFIT5 HERC5 MX1 0.972458 OAS1 TYKI SP110 0.972445 EPSTI1 OAS1 CIG5 0.972368 CIG5 PARP9 IFIT1 0.972329 IFIT4 OAS2 G1P2 0.972297 IFIT4 IRF7 IFI44 0.972137 HERC5 IFIT1 RIGE 0.97204 IFI44L PARP9 RIGE 0.971994 RIG1 CIG5 MX1 0.971955 CIG5 IFI44 SAMD9L 0.971908 CHMP5 IFIT1 ZBP1 0.971907 CIG5 SAMD9L ZBP1 0.971889 G1P2 OAS1 PARP9 0.971807 IRF7 PARP9 IFIT1 0.97179 OAS3 TYKI MX1 0.971782 OAS2 HERC5 CHMP5 0.97176 IRF7 HERC5 PARP9 0.971671 IFIT4 G1P2 PARP9 0.971625 EPSTI1 TYKI CHMP5 0.971602 IRF7 IFI44 MX1 0.971595 OAS1 OASL SAMD9L 0.971575 IFIT4 OAS2 CHMP5 0.971528 IFI44L G1P2 IRF7 0.971506 OAS1 HERC5 SP110 0.971466 RIG1 OASL TYKI 0.971392 IRF7 PARP9 TYKI 0.971348 IFIT4 OAS1 OAS3 0.971335 G1P2 CHMP5 ZBP1 0.971335 IFIT4 HERC5 SP110 0.971301 IFI44 TYKI SP110 0.971298 OAS2 IRF7 HERC5 0.97127 IFIT4 OAS2 IFIT1 0.971233 IFI44L PARP9 SP110 0.971191 IFIT5 OAS1 OAS3 0.971185 OAS2 IRF7 IFIT1 0.971184 OAS2 IFI44 PARP9 0.971174 IFI44L PARP9 ZBP1 0.971145 G1P2 CHMP5 SP110 0.971088 OAS1 HERC5 SAMD9L 0.971083 G1P2 CIG5 PARP9 0.971042 IFIT5 PARP9 XIAP 0.971027 EPSTI1 CHMP5 MX1 0.970954 G1P2 SP110 XIAP 0.970897 OASL HERC5 XIAP 0.970881 RIG1 IFIT1 ZBP1 0.97081 G1P2 OASL XIAP 0.970803 OAS2 PARP9 TYKI 0.970766 IFI44L IFIT4 OAS1 0.970742 IFIT5 G1P2 MX1 0.970738 EPSTI1 CIG5 HERC5 0.970734 EPSTI1 OAS1 PARP9 0.970723 HERC5 TYKI RIGE 0.970716 OAS1 OAS3 HERC5 0.970715 G1P2 IFIT1 RIGE 0.970712 IFIT4 IRF7 XIAP 0.970712 HERC5 CHMP5 SP110 0.970697 IFI44L OAS3 RIGE 0.970693 RIG1 CIG5 IFI44 0.970657 EPSTI1 OASL SAMD9L 0.970657 RIG1 G1P2 ZBP1 0.970629 RIG1 HERC5 ZBP1 0.970593 IFI44 SAMD9L ZBP1 0.970587 OAS1 IRF7 XIAP 0.970567 IFIT4 IFI44 MX1 0.970564 OAS1 OASL TYKI 0.970536 OAS1 OASL IFI44 0.970435 OAS1 OAS3 SAMD9L 0.970395 OAS1 IRF7 ZBP1 0.970393 IFI44L TYKI XIAP 0.970382 HERC5 XIAP ZBP1 0.970322 OAS2 CHMP5 IFIT1 0.970286 EPSTI1 OAS1 XIAP 0.970174 IFI44L IRF7 TYKI 0.970096 IFI44L HERC5 MX1 0.970092 PARP9 MX1 XIAP 0.970089 IFIT5 EPSTI1 RIG1 0.970015 IFIT5 IFIT4 PARP9 0.97001 G1P2 OAS3 IFIT1 0.96993 OAS3 HERC5 MX1 0.969845 OASL MX1 XIAP 0.969812 OAS1 IFI44 ZBP1 0.969803 G1P2 HERC5 RIGE 0.969762 IFIT5 PARP9 SP110 0.969753 G1P2 OAS3 HERC5 0.969712 OAS1 MX1 RIGE 0.969615 HERC5 PARP9 MX1 0.969607 IFI44 IFIT1 XIAP 0.969589 RIG1 OASL HERC5 0.969589 CIG5 TYKI SP110 0.969581 G1P2 IRF7 SP110 0.969568 IFIT5 IFI44L RIGE 0.969542 IFI44 HERC5 XIAP 0.96949 RIG1 IFI44 ZBP1 0.969468 IFIT5 HERC5 IFIT1 0.969441 IRF7 IFI44 HERC5 0.96943 RIG1 OAS1 HERC5 0.969339 IFIT5 TYKI XIAP 0.969273 EPSTI1 G1P2 OASL 0.969257 IFIT5 G1P2 IFIT1 0.969226 TYKI MX1 RIGE 0.969116 OAS3 PARP9 CHMP5 0.969112 EPSTI1 G1P2 CHMP5 0.96899 IFIT4 SAMD9L RIGE 0.968926 IFIT4 OAS1 SP110 0.968908 OAS2 CIG5 TYKI 0.968886 EPSTI1 CIG5 IFIT1 0.968832 IFIT4 RIG1 IRF7 0.968749 OASL IRF7 MX1 0.968693 IFIT4 IFIT1 SP110 0.968688 OAS2 OAS1 IFI44 0.968687 OAS2 RIG1 SAMD9L 0.968678 IFIT5 EPSTI1 SAMD9L 0.968673 OAS1 CHMP5 ZBP1 0.968667 IFI44L OAS1 SP110 0.968637 EPSTI1 RIG1 OAS1 0.968633 G1P2 OAS1 OAS3 0.968589 IFIT4 IFI44 HERC5 0.968562 IFI44 PARP9 RIGE 0.96854 IRF7 SAMD9L SP110 0.96853 OASL CIG5 TYKI 0.968523 EPSTI1 HERC5 CHMP5 0.96846 OAS2 G1P2 CHMP5 0.968446 IRF7 OAS3 SAMD9L 0.968439 G1P2 OASL IRF7 0.968413 EPSTI1 OASL IFIT1 0.968391 IFIT4 OAS3 HERC5 0.968353 IFIT5 IRF7 TYKI 0.968333 RIG1 OAS1 IRF7 0.968329 EPSTI1 IFIT1 ZBP1 0.968297 OASL CIG5 SAMD9L 0.968278 IRF7 MX1 ZBP1 0.968177 OAS1 HERC5 PARP9 0.968172 G1P2 PARP9 TYKI 0.968154 CHMP5 IFIT1 SP110 0.968058 IFIT4 CHMP5 SP110 0.968014 IFI44L IFIT1 MX1 0.967969 IFIT4 OAS2 MX1 0.967961 IRF7 CHMP5 XIAP 0.967909 IFIT5 OAS1 ZBP1 0.967889 IRF7 IFI44 IFIT1 0.967883 IFI44L HERC5 IFIT1 0.967852 OAS2 IFI44 SAMD9L 0.967841 OAS2 G1P2 IRF7 0.967815 EPSTI1 PARP9 MX1 0.967795 EPSTI1 HERC5 ZBP1 0.967772 OASL PARP9 CHMP5 0.967676 G1P2 IFI44 XIAP 0.967671 PARP9 SAMD9L ZBP1 0.967633 IFIT5 TYKI MX1 0.967584 OAS2 EPSTI1 G1P2 0.967581 IFIT4 OAS3 IFIT1 0.967551 IFIT5 OAS2 OAS1 0.967489 IFIT5 IFI44L OAS3 0.967466 OAS3 IFIT1 MX1 0.967409 IFIT5 SAMD9L SP110 0.967392 IFIT4 PARP9 MX1 0.967359 EPSTI1 OAS1 ZBP1 0.967286 IFIT5 PARP9 RIGE 0.967265 OAS1 SAMD9L XIAP 0.967252 PARP9 IFIT1 MX1 0.967202 OASL PARP9 IFIT1 0.967188 IFIT4 PARP9 XIAP 0.967184 G1P2 OAS1 RIGE 0.967087 IFI44L PARP9 XIAP 0.967006 IRF7 HERC5 SP110 0.966994 IFIT5 G1P2 HERC5 0.96692 IFI44L IFIT4 SAMD9L 0.966918 EPSTI1 G1P2 SP110 0.966913 IFIT4 EPSTI1 CHMP5 0.966844 OAS2 OAS1 CHMP5 0.966812 EPSTI1 IFI44 PARP9 0.966774 IFIT4 IFI44 IFIT1 0.966763 CIG5 SAMD9L CHMP5 0.966661 IFI44L IFIT4 PARP9 0.966617 IFIT5 RIG1 SP110 0.966575 EPSTI1 CIG5 MX1 0.966555 EPSTI1 CHMP5 IFIT1 0.966528 OAS2 IFIT1 XIAP 0.966404 MX1 XIAP ZBP1 0.966334 HERC5 MX1 RIGE 0.966315 IFIT5 OAS1 RIGE 0.966293 G1P2 PARP9 MX1 0.966277 IFI44L TYKI MX1 0.96627 IFI44 PARP9 ZBP1 0.966234 OAS1 CIG5 ZBP1 0.966217 IFIT4 G1P2 IFI44 0.966203 IFIT4 MX1 SP110 0.966196 OAS2 OAS1 IRF7 0.966139 IFIT4 CHMP5 XIAP 0.966104 IFIT5 IFIT4 SAMD9L 0.966044 RIG1 OASL MX1 0.966034 IFIT5 IRF7 PARP9 0.96594 G1P2 IRF7 PARP9 0.965876 OAS2 RIG1 IFI44 0.965818 IFI44L G1P2 MX1 0.96579 IRF7 IFIT1 SP110 0.965745 OAS2 EPSTI1 SAMD9L 0.965666 CHMP5 MX1 XIAP 0.965604 OAS2 PARP9 IFIT1 0.965491 EPSTI1 OAS1 IFI44 0.96548 OAS2 IRF7 MX1 0.965404 OAS1 SAMD9L RIGE 0.965336 IFIT1 SP110 XIAP 0.965321 RIG1 G1P2 OASL 0.965315 IFI44L OAS1 MX1 0.965307 G1P2 IRF7 IFI44 0.965102 IFIT5 TYKI IFIT1 0.965094 IFI44L G1P2 HERC5 0.965057 IFI44L G1P2 IFIT1 0.965022 IFIT5 SP110 RIGE 0.965009 EPSTI1 OASL HERC5 0.964998 OAS2 RIG1 IFIT1 0.964968 IFI44L IRF7 SAMD9L 0.964937 OAS3 PARP9 SAMD9L 0.964908 IFIT4 IFI44 TYKI 0.964883 PARP9 TYKI SP110 0.964876 IFIT5 IFIT4 RIG1 0.964868 EPSTI1 OAS3 TYKI 0.964834 IFI44L IFIT4 RIG1 0.964794 IFIT1 MX1 RIGE 0.96478 OAS2 SAMD9L XIAP 0.964778 IFIT5 IFIT4 OAS1 0.964745 OASL PARP9 TYKI 0.96474 OAS1 SAMD9L TYKI 0.964718 EPSTI1 OAS3 SAMD9L 0.964666 CIG5 PARP9 MX1 0.96462 OAS2 G1P2 XIAP 0.964584 G1P2 TYKI RIGE 0.964575 OAS1 OAS3 TYKI 0.964457 SAMD9L CHMP5 ZBP1 0.964434 IFI44L TYKI IFIT1 0.964427 G1P2 OAS3 TYKI 0.964415 IFIT4 TYKI RIGE 0.964415 IFIT5 PARP9 IFIT1 0.964404 IFI44 HERC5 MX1 0.964284 IFI44L OAS1 IRF7 0.964253 OAS1 IRF7 PARP9 0.964194 IFIT5 OASL RIGE 0.964094 IFIT5 PARP9 MX1 0.963954 G1P2 CIG5 ZBP1 0.963938 IFIT5 OAS1 OASL 0.963852 IRF7 CHMP5 MX1 0.963787 IFIT5 EPSTI1 OAS1 0.963774 OAS1 PARP9 XIAP 0.963475 OAS1 HERC5 RIGE 0.963465 EPSTI1 MX1 ZBP1 0.963452 EPSTI1 OASL MX1 0.963447 IRF7 PARP9 MX1 0.963413 IFI44 TYKI XIAP 0.963301 G1P2 MX1 RIGE 0.96322 EPSTI1 IFI44 SAMD9L 0.963203 OAS1 PARP9 SAMD9L 0.963196 IFI44L OAS1 IFIT1 0.963135 IFI44L IRF7 PARP9 0.963058 OAS1 SAMD9L SP110 0.963012 IFIT5 IRF7 SAMD9L 0.963 EPSTI1 OAS1 CHMP5 0.962935 IFIT4 IRF7 CHMP5 0.962925 IFIT4 EPSTI1 XIAP 0.96284 CIG5 HERC5 ZBP1 0.962817 PARP9 TYKI ZBP1 0.96278 OASL CIG5 IFIT1 0.962747 OAS1 PARP9 TYKI 0.962615 IFI44L HERC5 TYKI 0.962603 OAS2 EPSTI1 IFIT1 0.962552 CIG5 PARP9 CHMP5 0.962508 IFI44L RIG1 IRF7 0.962495 IFI44L SAMD9L XIAP 0.962462 IFI44L IFI44 RIGE 0.9624 IRF7 HERC5 CHMP5 0.962383 OASL SAMD9L ZBP1 0.962363 OAS2 CIG5 SAMD9L 0.962348 OAS2 RIG1 HERC5 0.962318 OAS2 HERC5 XIAP 0.962291 IFIT5 SAMD9L MX1 0.962201 CIG5 IFIT1 ZBP1 0.962115 HERC5 SP110 XIAP 0.962086 RIG1 IFIT1 SP110 0.962019 OAS2 OAS1 PARP9 0.962018 RIG1 CIG5 CHMP5 0.961991 IFI44 IFIT1 MX1 0.961953 IFIT5 OAS1 MX1 0.961952 HERC5 CHMP5 XIAP 0.961934 RIG1 HERC5 SP110 0.961903 OAS3 SAMD9L XIAP 0.961841 RIG1 SAMD9L SP110 0.961804 CHMP5 IFIT1 XIAP 0.961773 G1P2 OAS3 MX1 0.961665 TYKI CHMP5 XIAP 0.961658 TYKI SP110 ZBP1 0.961568 OAS2 HERC5 PARP9 0.961517 G1P2 IFI44 MX1 0.961483 IFIT4 OAS1 IFI44 0.961474 IRF7 IFI44 TYKI 0.961401 IFI44L RIG1 XIAP 0.961392 SAMD9L SP110 XIAP 0.961343 PARP9 SAMD9L SP110 0.961334 IFIT5 IFI44L OASL 0.961265 OAS2 G1P2 PARP9 0.961245 OASL HERC5 PARP9 0.961238 RIG1 MX1 ZBP1 0.96122 OAS2 RIG1 G1P2 0.961201 IRF7 OAS3 IFIT1 0.961186 OAS2 EPSTI1 OAS1 0.96115 IFI44 SAMD9L SP110 0.961138 OAS1 XIAP ZBP1 0.961114 IFIT4 G1P2 OAS3 0.961085 IFIT5 RIG1 XIAP 0.961054 IFIT5 SAMD9L XIAP 0.961053 IFI44 HERC5 IFIT1 0.960963 IFIT5 RIG1 IRF7 0.96093 IFI44L CHMP5 RIGE 0.960881 IFIT4 OAS3 MX1 0.960838 IFIT5 OAS3 RIGE 0.960806 OAS2 EPSTI1 HERC5 0.960756 OAS2 MX1 XIAP 0.960748 IFIT4 TYKI CHMP5 0.960741 EPSTI1 RIG1 IFI44 0.960722 IFIT5 HERC5 TYKI 0.960702 OASL CIG5 HERC5 0.960689 IFI44L SAMD9L MX1 0.960664 IFIT5 IFI44L CIG5 0.960571 IFIT4 EPSTI1 IRF7 0.960461 IRF7 MX1 SP110 0.96046 IFI44L OAS1 XIAP 0.960455 IFIT5 CHMP5 RIGE 0.960416 IFIT5 IFI44 RIGE 0.960385 IFIT5 RIG1 MX1 0.960368 MX1 SP110 XIAP 0.960338 IRF7 OAS3 HERC5 0.960332 IRF7 OAS3 TYKI 0.960205 IFI44 PARP9 SP110 0.960125 OASL TYKI ZBP1 0.960125 IRF7 CHMP5 IFIT1 0.960021 OAS2 SAMD9L CHMP5 0.959993 G1P2 IFI44 HERC5 0.959978 IFIT4 CHMP5 MX1 0.959927 IFI44 TYKI MX1 0.959842 G1P2 OASL CIG5 0.959832 IFIT4 CIG5 XIAP 0.959816 IFIT4 OAS1 RIGE 0.959814 OAS2 TYKI ZBP1 0.959811 IRF7 TYKI CHMP5 0.959787 OAS3 IFIT1 XIAP 0.959775 OAS2 OAS1 CIG5 0.959672 G1P2 CHMP5 XIAP 0.959471 G1P2 IFI44 IFIT1 0.959467 IFI44L PARP9 IFIT1 0.959464 G1P2 OASL PARP9 0.959415 IFIT5 HERC5 PARP9 0.959387 OAS1 OASL IRF7 0.959375 OAS1 IFI44 SP110 0.959304 IFI44 PARP9 XIAP 0.959285 IFIT5 OAS1 IFIT1 0.959283 PARP9 CHMP5 RIGE 0.959251 OAS3 TYKI XIAP 0.959059 IFIT5 IFI44 OAS3 0.959005 IFIT5 OAS3 CHMP5 0.959002 RIG1 CHMP5 ZBP1 0.958994 IFIT4 IFIT1 RIGE 0.958926 EPSTI1 PARP9 XIAP 0.958805 RIG1 OAS1 ZBP1 0.958689 OAS1 IFI44 MX1 0.958663 EPSTI1 OAS3 IFIT1 0.958634 IFIT5 G1P2 PARP9 0.95861 OAS2 EPSTI1 MX1 0.958508 PARP9 IFIT1 ZBP1 0.958503 IFIT4 HERC5 CHMP5 0.958451 G1P2 CIG5 SP110 0.958403 IFI44L PARP9 MX1 0.958264 OAS1 CHMP5 SP110 0.95826 G1P2 PARP9 SP110 0.958153 OAS1 TYKI RIGE 0.958151 IFIT4 HERC5 RIGE 0.958132 RIG1 OAS1 TYKI 0.958104 IFIT4 IRF7 PARP9 0.958024 IFIT4 EPSTI1 PARP9 0.957986 IFIT5 SAMD9L IFIT1 0.957766 RIG1 IRF7 XIAP 0.957764 CIG5 SAMD9L SP110 0.957721 IFI44L IFI44 OAS3 0.957601 IFIT5 G1P2 TYKI 0.9576 IFI44L HERC5 PARP9 0.957553 RIG1 OAS3 SAMD9L 0.957356 EPSTI1 OAS1 OASL 0.957294 IFIT4 XIAP ZBP1 0.95721 IFI44L SAMD9L IFIT1 0.957107 IFI44L G1P2 TYKI 0.957049 OAS2 RIG1 MX1 0.957032 IFI44 TYKI IFIT1 0.957022 CIG5 PARP9 XIAP 0.957014 IFIT4 IRF7 ZBP1 0.956993 IFI44L G1P2 OAS1 0.956925 OAS1 OASL CIG5 0.956894 IFIT4 IFI44 PARP9 0.95679 EPSTI1 OAS3 HERC5 0.956754 IFIT4 G1P2 RIGE 0.956716 IFIT4 IRF7 CIG5 0.956703 IFIT4 OAS1 CHMP5 0.956662 IFI44L OAS1 HERC5 0.956626 G1P2 IRF7 CHMP5 0.956597 IFIT4 IFI44 SAMD9L 0.956274 IFIT5 IFI44L ZBP1 0.956233 IFI44L RIG1 MX1 0.956172 IFIT4 CHMP5 IFIT1 0.95615 IFIT5 OAS1 IRF7 0.956078 OASL CIG5 MX1 0.956076 OASL IFIT1 ZBP1 0.956072 OAS2 G1P2 CIG5 0.956019 OAS2 PARP9 CHMP5 0.956009 G1P2 PARP9 ZBP1 0.955951 OAS2 OASL TYKI 0.955901 OAS1 IRF7 IFI44 0.955882 IFI44 HERC5 TYKI 0.955752 OAS3 HERC5 XIAP 0.955729 RIG1 PARP9 IFIT1 0.955722 OAS2 CIG5 IFIT1 0.955705 IFIT4 OASL XIAP 0.955698 IFIT4 CIG5 PARP9 0.955687 OASL PARP9 MX1 0.955668 PARP9 IFIT1 SP110 0.955597 IFIT4 EPSTI1 RIG1 0.95557 EPSTI1 OAS1 OAS3 0.955534 OAS2 TYKI SP110 0.955523 IFIT4 G1P2 CHMP5 0.955509 OAS1 IFI44 IFIT1 0.955489 IFIT5 IFI44L OAS2 0.955474 RIG1 IFI44 SP110 0.955462 IFIT5 G1P2 SAMD9L 0.955415 RIG1 MX1 SP110 0.955384 CIG5 MX1 ZBP1 0.955366 IFI44L HERC5 SAMD9L 0.955348 EPSTI1 SAMD9L CHMP5 0.955332 RIG1 OAS1 XIAP 0.955331 EPSTI1 IRF7 XIAP 0.95532 IFIT5 RIG1 IFIT1 0.955282 EPSTI1 SAMD9L SP110 0.955279 EPSTI1 G1P2 OAS3 0.955231 OAS2 CIG5 HERC5 0.955226 TYKI CHMP5 MX1 0.955217 IFI44L OAS3 CHMP5 0.955174 SAMD9L RIGE XIAP 0.955126 OAS3 PARP9 IFIT1 0.955055 RIG1 PARP9 SAMD9L 0.955049 HERC5 PARP9 ZBP1 0.954901 OAS2 SAMD9L ZBP1 0.954865 EPSTI1 IFIT1 SP110 0.954814 IFIT5 OAS1 SP110 0.954676 OAS1 PARP9 ZBP1 0.954667 SAMD9L CHMP5 SP110 0.954657 IFI44L G1P2 SAMD9L 0.954471 IRF7 PARP9 XIAP 0.954463 CIG5 OAS3 SAMD9L 0.95446 OAS1 IRF7 OAS3 0.954415 HERC5 CHMP5 MX1 0.954364 OAS1 IFI44 XIAP 0.954344 IRF7 IFI44 SAMD9L 0.954318 OAS1 OASL XIAP 0.954263 IFI44L OASL IFI44 0.954204 IFI44 SAMD9L XIAP 0.954127 OAS2 PARP9 MX1 0.9541 OAS1 CHMP5 MX1 0.95402 OAS2 OASL SAMD9L 0.953851 IRF7 IFI44 PARP9 0.953769 OAS2 OAS1 XIAP 0.953577 IFI44L G1P2 PARP9 0.953542 EPSTI1 HERC5 SP110 0.953434 IRF7 SAMD9L RIGE 0.953308 EPSTI1 PARP9 CHMP5 0.953256 OAS1 IRF7 CHMP5 0.953118 IFIT5 HERC5 SAMD9L 0.95311 IFIT5 G1P2 OAS1 0.953008 IFI44 SAMD9L MX1 0.952969 IFIT5 OAS1 XIAP 0.952878 IFIT4 MX1 RIGE 0.952876 IFI44L RIG1 IFIT1 0.952657 CIG5 HERC5 SP110 0.95255 IFIT4 OASL IRF7 0.952437 IFIT5 PARP9 TYKI 0.952387 OAS1 OASL PARP9 0.952351 IFIT5 OASL IFI44 0.952334 TYKI CHMP5 IFIT1 0.952291 EPSTI1 IRF7 PARP9 0.95219 IRF7 CIG5 XIAP 0.952171 IFIT1 RIGE XIAP 0.952097 CIG5 IFIT1 SP110 0.952015 G1P2 OASL ZBP1 0.951985 EPSTI1 RIG1 IRF7 0.951946 IFI44L PARP9 TYKI 0.951921 IFI44 PARP9 MX1 0.951919 OAS3 PARP9 TYKI 0.951916 CIG5 OAS3 TYKI 0.951891 G1P2 IFI44 TYKI 0.951838 OAS2 RIG1 CHMP5 0.951825 EPSTI1 TYKI RIGE 0.951667 RIG1 PARP9 TYKI 0.951655 HERC5 PARP9 SP110 0.951639 IFIT4 RIG1 ZBP1 0.951613 RIG1 HERC5 PARP9 0.951503 G1P2 OAS1 IFI44 0.951439 IRF7 OAS3 MX1 0.951423 IFI44 PARP9 IFIT1 0.95141 CHMP5 IFIT1 MX1 0.951388 EPSTI1 MX1 SP110 0.951254 OAS2 RIG1 OAS1 0.951245 IFI44L RIG1 HERC5 0.951245 IFIT5 CIG5 IFI44 0.951244 TYKI RIGE XIAP 0.951171 EPSTI1 SAMD9L RIGE 0.951147 HERC5 TYKI CHMP5 0.951145 EPSTI1 OAS3 MX1 0.951138 HERC5 CHMP5 IFIT1 0.951107 IFI44L CIG5 IFI44 0.951044 IFI44L OASL CHMP5 0.951043 G1P2 SP110 ZBP1 0.951027 SAMD9L SP110 ZBP1 0.95089 G1P2 CHMP5 MX1 0.950868 OAS2 OASL IFIT1 0.950862 PARP9 CHMP5 ZBP1 0.950852 OAS3 HERC5 PARP9 0.95078 EPSTI1 RIG1 XIAP 0.950771 OASL TYKI SP110 0.950742 IFIT4 RIG1 CIG5 0.950667 OAS1 IRF7 SP110 0.950651 OAS1 CHMP5 IFIT1 0.950645 IFIT5 IFI44L EPSTI1 0.950585 IFIT5 OASL CHMP5 0.950564 OAS1 CHMP5 XIAP 0.950413 OAS3 MX1 XIAP 0.950368 OASL HERC5 ZBP1 0.950235 IFI44 HERC5 PARP9 0.950187 OAS1 IFI44 HERC5 0.95016 RIG1 OAS1 SAMD9L 0.950071 G1P2 HERC5 CHMP5 0.949965 RIG1 OAS3 IFIT1 0.9499 IRF7 CIG5 PARP9 0.949776 IFI44L SAMD9L TYKI 0.949773 IFI44 CHMP5 RIGE 0.949687 G1P2 OAS3 XIAP 0.949642 OAS1 CIG5 SP110 0.949578 OAS2 CIG5 MX1 0.949555 IFIT5 OAS1 HERC5 0.949513 OAS1 OAS3 PARP9 0.94951 G1P2 IRF7 OAS3 0.949402 G1P2 CHMP5 IFIT1 0.949251 IFIT5 RIG1 HERC5 0.948959 IFIT4 RIG1 IFI44 0.948886 IFI44L OAS1 TYKI 0.948871 RIG1 IFI44 XIAP 0.94863 IFIT5 PARP9 SAMD9L 0.948596 IFI44 SAMD9L IFIT1 0.948585 IFIT4 OASL PARP9 0.948562 IFIT4 EPSTI1 ZBP1 0.948539 IFIT5 RIG1 G1P2 0.948086 OAS1 CIG5 OAS3 0.947983 G1P2 IFI44 PARP9 0.947968 IFIT5 IFI44L SP110 0.947938 EPSTI1 CIG5 PARP9 0.947921 EPSTI1 RIG1 CHMP5 0.947831 IFIT5 IFI44 ZBP1 0.947787 IFI44L PARP9 SAMD9L 0.947734 G1P2 IFI44 SAMD9L 0.947721 IFI44L OAS1 PARP9 0.947446 IFI44 HERC5 SAMD9L 0.947347 OAS2 IFIT1 ZBP1 0.947303 IFIT4 EPSTI1 CIG5 0.947143 RIG1 G1P2 PARP9 0.947042 IFIT4 RIG1 OASL 0.946997 OAS2 G1P2 ZBP1 0.946916 CIG5 OAS3 IFIT1 0.946822 G1P2 RIGE XIAP 0.946802 OAS1 OAS3 XIAP 0.946769 IFIT5 SAMD9L TYKI 0.946742 RIG1 CIG5 XIAP 0.946738 CIG5 SAMD9L RIGE 0.946558 IRF7 IFIT1 RIGE 0.946462 IFI44L IFI44 ZBP1 0.946452 PARP9 MX1 ZBP1 0.946362 IFIT5 OAS2 IFI44 0.946333 EPSTI1 G1P2 RIGE 0.946322 HERC5 RIGE XIAP 0.946188 CIG5 MX1 SP110 0.946153 RIG1 SAMD9L RIGE 0.946083 RIG1 IRF7 IFI44 0.946068 IRF7 SAMD9L CHMP5 0.946026 G1P2 TYKI CHMP5 0.945962 RIG1 OAS3 HERC5 0.945918 RIG1 IRF7 CIG5 0.945803 OASL MX1 ZBP1 0.945774 G1P2 OAS1 CHMP5 0.945734 IFIT4 OAS2 IRF7 0.945691 CIG5 OAS3 HERC5 0.945585 IFIT4 SAMD9L CHMP5 0.945499 IFIT5 CIG5 CHMP5 0.945489 EPSTI1 OAS1 SP110 0.945479 IRF7 TYKI RIGE 0.945447 RIG1 IFI44 MX1 0.945413 EPSTI1 IFIT1 RIGE 0.945395 IFIT4 OAS2 PARP9 0.945338 IFI44L RIG1 G1P2 0.945334 IFI44 OAS3 CHMP5 0.945317 OAS2 OAS1 ZBP1 0.945291 RIG1 OAS3 TYKI 0.945221 SAMD9L CHMP5 XIAP 0.945205 PARP9 SAMD9L RIGE 0.945185 OAS2 G1P2 OASL 0.944851 PARP9 CHMP5 XIAP 0.944816 IFIT4 EPSTI1 OASL 0.944671 IFI44L OAS2 IFI44 0.944632 IFIT4 PARP9 ZBP1 0.944622 EPSTI1 CIG5 XIAP 0.944456 RIG1 OAS1 OASL 0.944438 OAS1 HERC5 CHMP5 0.94431 IFI44 PARP9 TYKI 0.944208 PARP9 CHMP5 SP110 0.944124 IFIT1 SP110 ZBP1 0.944046 IFI44L CIG5 CHMP5 0.943778 IFIT5 IFI44L IFIT4 0.943771 PARP9 MX1 SP110 0.943665 RIG1 CHMP5 SP110 0.943533 OAS2 OASL HERC5 0.9435 OAS1 OASL ZBP1 0.9435 IFIT4 OAS2 XIAP 0.943449 MX1 RIGE XIAP 0.943426 CIG5 TYKI RIGE 0.943328 EPSTI1 IRF7 CIG5 0.943287 IRF7 HERC5 RIGE 0.943132 RIG1 PARP9 MX1 0.942814 OAS2 HERC5 ZBP1 0.942715 IFIT4 RIG1 PARP9 0.942684 SAMD9L CHMP5 MX1 0.942597 OASL SAMD9L SP110 0.942585 G1P2 OAS3 PARP9 0.942554 OAS1 IFI44 TYKI 0.942437 OASL IFIT1 SP110 0.942318 IFI44L EPSTI1 IFI44 0.942267 OAS3 SAMD9L ZBP1 0.942149 OAS1 PARP9 SP110 0.942068 OAS1 SP110 XIAP 0.942012 IFI44L RIG1 TYKI 0.94201 IFIT5 OAS1 PARP9 0.94199 G1P2 OASL SP110 0.941717 IFI44 SAMD9L TYKI 0.941631 IFIT4 CIG5 ZBP1 0.941466 EPSTI1 HERC5 RIGE 0.941431 IFIT5 OAS1 TYKI 0.941419 IFIT5 EPSTI1 IFI44 0.941395 IFI44L OAS1 SAMD9L 0.941117 OAS2 OASL MX1 0.941065 IFIT5 CHMP5 ZBP1 0.940941 OAS2 G1P2 SP110 0.940753 OAS3 PARP9 MX1 0.940695 OASL IFI44 CHMP5 0.940462 RIG1 IFI44 IFIT1 0.940444 IRF7 XIAP ZBP1 0.940387 IFIT4 OAS3 XIAP 0.940303 OAS1 TYKI CHMP5 0.940259 HERC5 SP110 ZBP1 0.940142 G1P2 CIG5 OAS3 0.939919 OAS1 IFI44 PARP9 0.939836 IFIT4 PARP9 CHMP5 0.9396 RIG1 IFI44 HERC5 0.939599 IFIT4 IRF7 OAS3 0.939488 G1P2 IRF7 RIGE 0.939474 IFIT5 IFI44L XIAP 0.939166 EPSTI1 OAS1 RIGE 0.938921 RIG1 PARP9 XIAP 0.938797 EPSTI1 IRF7 ZBP1 0.938775 IFIT5 OAS2 CHMP5 0.938637 IFIT4 OASL CIG5 0.938552 EPSTI1 MX1 RIGE 0.938432 IFIT5 IFI44L IRF7 0.938421 OASL PARP9 XIAP 0.938359 IFIT5 IFI44L MX1 0.93825 CIG5 IFIT1 RIGE 0.938229 EPSTI1 RIG1 PARP9 0.938162 IFIT5 RIG1 TYKI 0.938067 IFI44 PARP9 SAMD9L 0.937964 IRF7 PARP9 CHMP5 0.937956 SAMD9L CHMP5 IFIT1 0.937945 IFI44L IFI44 SP110 0.937911 OAS3 TYKI ZBP1 0.937748 IFIT4 OAS3 PARP9 0.937712 CIG5 OAS3 MX1 0.937685 IFI44L CHMP5 ZBP1 0.937606 RIG1 OAS1 PARP9 0.937438 OAS2 SAMD9L SP110 0.937426 IRF7 MX1 RIGE 0.937279 OAS2 OAS1 OASL 0.937248 RIG1 IFIT1 RIGE 0.93718 OAS2 MX1 ZBP1 0.937132 G1P2 SAMD9L CHMP5 0.936982 EPSTI1 XIAP ZBP1 0.936697 RIG1 G1P2 IFI44 0.936637 OAS1 CIG5 RIGE 0.936614 OASL IRF7 XIAP 0.936603 PARP9 IFIT1 RIGE 0.936593 HERC5 SAMD9L CHMP5 0.93654 IFIT4 SP110 XIAP 0.936501 IFIT4 OAS2 EPSTI1 0.936231 RIG1 CIG5 PARP9 0.936225 IFIT4 EPSTI1 OAS3 0.936192 IFIT5 IFI44 SP110 0.936081 PARP9 CHMP5 IFIT1 0.935858 SAMD9L TYKI CHMP5 0.935842 OAS2 IFIT1 SP110 0.935741 OAS1 IRF7 RIGE 0.935686 OASL OAS3 SAMD9L 0.935639 CIG5 HERC5 RIGE 0.935444 OAS1 RIGE XIAP 0.935361 G1P2 CIG5 RIGE 0.935304 IFIT5 IFI44L IFIT1 0.935275 PARP9 CHMP5 MX1 0.935232 RIG1 OAS3 MX1 0.935175 IFI44L OAS2 CHMP5 0.934781 RIG1 OAS1 OAS3 0.934681 OASL HERC5 SP110 0.934566 PARP9 TYKI CHMP5 0.934504 OAS3 IFIT1 ZBP1 0.934375 SAMD9L RIGE ZBP1 0.934283 HERC5 PARP9 CHMP5 0.93411 IFIT5 IFIT4 IFI44 0.934012 EPSTI1 OASL PARP9 0.933922 OAS3 TYKI SP110 0.933864 CIG5 IFI44 CHMP5 0.933838 MX1 SP110 ZBP1 0.933692 RIG1 CHMP5 XIAP 0.933629 OAS1 IFI44 SAMD9L 0.933607 IFI44L IFIT4 IFI44 0.933553 PARP9 TYKI RIGE 0.933515 IFIT4 IRF7 SP110 0.933498 OAS2 EPSTI1 PARP9 0.933446 OAS1 SP110 ZBP1 0.933405 OAS2 PARP9 XIAP 0.933338 IFIT5 EPSTI1 CHMP5 0.933165 EPSTI1 OASL XIAP 0.933115 IFIT4 OASL ZBP1 0.933099 EPSTI1 PARP9 ZBP1 0.932945 IFI44L EPSTI1 CHMP5 0.932873 OASL OAS3 IFIT1 0.932774 PARP9 XIAP ZBP1 0.932749 EPSTI1 RIG1 CIG5 0.93261 IFIT5 OAS1 SAMD9L 0.932602 OASL MX1 SP110 0.932194 IFIT4 OAS2 RIG1 0.932084 RIG1 TYKI RIGE 0.932067 RIG1 IRF7 ZBP1 0.931911 EPSTI1 OASL IRF7 0.931811 RIG1 G1P2 OAS3 0.931711 OAS2 IRF7 PARP9 0.931653 IFI44L RIG1 OAS1 0.931497 G1P2 PARP9 CHMP5 0.931468 IFIT5 RIG1 PARP9 0.931134 IFIT5 IFI44L HERC5 0.931073 RIG1 IRF7 CHMP5 0.930931 IFIT5 IFI44 XIAP 0.930929 OAS3 SAMD9L SP110 0.930851 OASL OAS3 TYKI 0.930816 IFIT5 IFI44 MX1 0.930811 IRF7 CIG5 ZBP1 0.930782 RIG1 IFI44 TYKI 0.930705 IFI44L IFI44 XIAP 0.930504 OASL IRF7 PARP9 0.930323 CIG5 XIAP ZBP1 0.930024 IFIT5 IFI44L G1P2 0.929939 OAS1 OAS3 ZBP1 0.92992 IFIT4 RIG1 CHMP5 0.929849 OAS2 HERC5 SP110 0.929752 CIG5 MX1 RIGE 0.929631 RIG1 HERC5 RIGE 0.929627 HERC5 PARP9 RIGE 0.929502 IFI44L RIG1 SAMD9L 0.929277 OAS3 HERC5 ZBP1 0.929262 IFIT4 PARP9 SP110 0.929202 IFI44L IFI44 MX1 0.929036 OAS1 PARP9 CHMP5 0.928969 IFI44L IRF7 IFI44 0.928905 TYKI RIGE ZBP1 0.928873 IFIT5 IRF7 IFI44 0.928864 IFIT4 OAS2 CIG5 0.928862 G1P2 PARP9 RIGE 0.928789 IFI44L RIG1 PARP9 0.928757 IFI44 CHMP5 ZBP1 0.928586 OAS2 OAS3 TYKI 0.928574 OASL CIG5 PARP9 0.928457 IFI44L CHMP5 SP110 0.928425 IFIT5 CHMP5 SP110 0.92804 OAS2 OAS3 SAMD9L 0.928004 RIG1 OAS1 SP110 0.927916 IRF7 PARP9 ZBP1 0.927757 RIG1 CHMP5 MX1 0.927685 OASL CIG5 XIAP 0.927452 IFIT5 IFI44 IFIT1 0.927301 RIG1 G1P2 RIGE 0.927147 OAS1 PARP9 RIGE 0.926871 CIG5 PARP9 ZBP1 0.926818 OAS2 EPSTI1 IRF7 0.926537 OAS3 IFIT1 SP110 0.926516 OAS2 IRF7 XIAP 0.926247 OAS2 MX1 SP110 0.926135 IFI44L IFI44 IFIT1 0.926123 OAS1 SAMD9L CHMP5 0.925906 OAS2 CIG5 PARP9 0.925828 EPSTI1 OAS3 PARP9 0.925671 G1P2 OAS3 ZBP1 0.925573 IFIT1 RIGE ZBP1 0.925539 IFIT4 RIGE XIAP 0.925317 OAS2 IFI44 CHMP5 0.925256 RIG1 XIAP ZBP1 0.925255 OASL IRF7 CIG5 0.925231 OASL OAS3 HERC5 0.92508 IFIT5 IFI44L TYKI 0.924932 EPSTI1 RIG1 ZBP1 0.924695 IFIT5 RIG1 SAMD9L 0.924337 OAS2 OAS3 IFIT1 0.924255 IFI44L IFI44 HERC5 0.924174 RIG1 IRF7 PARP9 0.923945 EPSTI1 CIG5 ZBP1 0.923914 OAS2 OAS1 SP110 0.923858 IFIT5 IFI44 HERC5 0.923703 IFIT5 G1P2 IFI44 0.923603 RIG1 MX1 RIGE 0.923568 IFIT4 CIG5 OAS3 0.92356 IFIT5 IFIT4 CHMP5 0.923303 EPSTI1 IFI44 CHMP5 0.923176 IFIT4 RIG1 OAS3 0.923081 RIG1 OASL XIAP 0.922837 RIG1 CHMP5 IFIT1 0.922695 PARP9 MX1 RIGE 0.922687 OAS2 SAMD9L RIGE 0.922634 IFIT5 IFI44L PARP9 0.92262 IFIT4 EPSTI1 SP110 0.922466 IFI44L G1P2 IFI44 0.922343 OAS3 PARP9 XIAP 0.921953 OAS2 EPSTI1 XIAP 0.921908 OAS2 TYKI RIGE 0.921747 IFIT4 OAS2 ZBP1 0.921651 RIG1 HERC5 CHMP5 0.92161 IFI44L IFIT4 CHMP5 0.921594 EPSTI1 IRF7 OAS3 0.921499 RIG1 OASL IRF7 0.921365 G1P2 RIGE ZBP1 0.921333 PARP9 SAMD9L CHMP5 0.92129 IFIT5 CHMP5 XIAP 0.921284 OAS3 MX1 ZBP1 0.921266 RIG1 TYKI CHMP5 0.92113 IFIT4 OAS2 OASL 0.921102 RIG1 OAS1 IFI44 0.921011 OASL SAMD9L RIGE 0.92072 OAS3 HERC5 SP110 0.920417 EPSTI1 OAS3 XIAP 0.920342 IFIT5 CHMP5 MX1 0.920248 OASL OAS3 MX1 0.920206 G1P2 OAS3 SP110 0.920122 G1P2 OASL OAS3 0.920062 IFIT4 CIG5 SP110 0.919544 IFI44L CHMP5 XIAP 0.919301 EPSTI1 OASL CIG5 0.91928 OAS1 OASL SP110 0.919179 IFIT5 IRF7 CHMP5 0.919067 OAS2 OAS1 OAS3 0.918994 IFI44L IFI44 TYKI 0.918961 OAS1 OASL OAS3 0.918852 HERC5 RIGE ZBP1 0.918551 OASL IFIT1 RIGE 0.91841 IFIT5 RIG1 OAS1 0.91814 OAS2 IRF7 CIG5 0.918041 IRF7 OAS3 XIAP 0.918037 IFIT5 IFI44 TYKI 0.917786 OAS1 RIGE ZBP1 0.917732 RIG1 G1P2 CHMP5 0.917667 IFI44L IRF7 CHMP5 0.917628 OAS2 IFIT1 RIGE 0.917465 OAS2 OAS3 HERC5 0.91737 IRF7 OAS3 PARP9 0.917026 IFI44L CHMP5 MX1 0.916997 IFIT4 IRF7 RIGE 0.916887 IFIT4 RIG1 SP110 0.916864 IFIT5 CHMP5 IFIT1 0.916571 OASL TYKI RIGE 0.916429 IFIT4 EPSTI1 RIGE 0.916258 EPSTI1 RIG1 OASL 0.916184 RIG1 IFI44 PARP9 0.916107 IFIT5 IFI44L OAS1 0.915943 RIG1 IFI44 SAMD9L 0.915918 IFI44 CHMP5 SP110 0.915791 PARP9 SP110 XIAP 0.915523 RIG1 OAS1 RIGE 0.915317 OAS2 CIG5 XIAP 0.915027 IFIT5 IFI44L SAMD9L 0.914239 IFI44L CHMP5 IFIT1 0.914106 IFIT5 IFI44 PARP9 0.913922 OAS1 OAS3 SP110 0.913805 IFI44L OAS1 IFI44 0.913685 OAS2 G1P2 OAS3 0.913341 OAS3 MX1 SP110 0.913024 MX1 RIGE ZBP1 0.91295 IFI44L IFI44 PARP9 0.912714 RIG1 CIG5 ZBP1 0.912402 IFIT5 HERC5 CHMP5 0.912293 IFIT4 SP110 ZBP1 0.912203 CIG5 OAS3 PARP9 0.912168 IFIT5 G1P2 CHMP5 0.912138 IFIT4 OAS3 ZBP1 0.912117 IFIT4 IFI44 CHMP5 0.912012 OAS2 RIG1 IRF7 0.911984 IRF7 SP110 XIAP 0.911965 TYKI SP110 RIGE 0.9118 IFI44L HERC5 CHMP5 0.911777 OAS2 OAS3 MX1 0.91137 OAS2 G1P2 RIGE 0.911317 IFIT4 PARP9 RIGE 0.911158 IFI44 CHMP5 XIAP 0.910766 OAS2 EPSTI1 CIG5 0.910517 OASL IRF7 ZBP1 0.910488 OASL XIAP ZBP1 0.909994 IFI44L TYKI CHMP5 0.909904 EPSTI1 PARP9 SP110 0.909711 IFI44 CHMP5 MX1 0.909689 IFIT5 TYKI CHMP5 0.90968 G1P2 OASL RIGE 0.90961 IFI44L G1P2 CHMP5 0.909576 IFIT5 OAS1 IFI44 0.909388 IFIT4 CIG5 RIGE 0.908925 OAS2 OAS1 RIGE 0.908806 OAS2 HERC5 RIGE 0.908751 OASL HERC5 RIGE 0.908541 CIG5 PARP9 SP110 0.908525 EPSTI1 OASL ZBP1 0.908429 RIG1 OAS1 CHMP5 0.90836 IFI44L IFI44 SAMD9L 0.907964 IRF7 IFI44 CHMP5 0.907863 CIG5 OAS3 XIAP 0.907513 IRF7 CIG5 OAS3 0.907333 IFIT4 OASL OAS3 0.906832 RIG1 OASL CIG5 0.90659 SAMD9L SP110 RIGE 0.906569 EPSTI1 SP110 XIAP 0.906534 IFIT5 IFI44 SAMD9L 0.90643 EPSTI1 CIG5 OAS3 0.906354 IFI44 CHMP5 IFIT1 0.906304 OASL MX1 RIGE 0.906245 IRF7 PARP9 SP110 0.906101 EPSTI1 IRF7 SP110 0.906008 IFIT4 OASL SP110 0.905978 OAS2 MX1 RIGE 0.90518 CIG5 SP110 XIAP 0.90499 IFIT1 SP110 RIGE 0.904324 IFI44 HERC5 CHMP5 0.904282 RIG1 OASL PARP9 0.904259 OAS3 SAMD9L RIGE 0.904065 IFI44L OAS1 CHMP5 0.903581 IRF7 CIG5 SP110 0.903302 G1P2 IFI44 CHMP5 0.903298 G1P2 SP110 RIGE 0.903287 OAS2 EPSTI1 RIG1 0.903249 OASL PARP9 ZBP1 0.902995 OAS2 OASL PARP9 0.902848 IFI44 TYKI CHMP5 0.902228 OAS1 OASL RIGE 0.901099 OAS2 IRF7 ZBP1 0.900596 OAS2 RIG1 PARP9 0.900166 OAS3 IFIT1 RIGE 0.900065 OASL CIG5 ZBP1 0.899594 EPSTI1 RIGE XIAP 0.899556 IFIT5 OAS1 CHMP5 0.89953 OAS2 RIG1 XIAP 0.899013 IFIT5 PARP9 CHMP5 0.898064 OAS2 OASL IRF7 0.898064 OAS3 TYKI RIGE 0.897749 OAS2 EPSTI1 ZBP1 0.897534 IFIT4 RIG1 RIGE 0.897168 EPSTI1 RIG1 OAS3 0.896978 OAS2 PARP9 ZBP1 0.896335 IFIT4 RIGE ZBP1 0.896273 OAS1 IFI44 CHMP5 0.896108 IFIT5 IFI44L RIG1 0.895894 IFI44L PARP9 CHMP5 0.895497 IFIT4 OAS2 OAS3 0.895401 OAS2 EPSTI1 OASL 0.895303 OAS2 OASL XIAP 0.895129 HERC5 SP110 RIGE 0.894807 EPSTI1 CIG5 SP110 0.894768 IFIT4 OAS2 SP110 0.894337 IRF7 RIGE XIAP 0.8943 RIG1 SAMD9L CHMP5 0.89381 IFI44L SAMD9L CHMP5 0.893745 PARP9 RIGE XIAP 0.89358 OAS2 XIAP ZBP1 0.893376 EPSTI1 IRF7 RIGE 0.893012 EPSTI1 PARP9 RIGE 0.892978 IFIT5 SAMD9L CHMP5 0.892943 RIG1 PARP9 ZBP1 0.892935 CIG5 RIGE XIAP 0.892719 IFIT4 OAS3 SP110 0.891861 MX1 SP110 RIGE 0.891301 OAS3 HERC5 RIGE 0.891101 RIG1 IRF7 OAS3 0.890525 OAS2 RIG1 CIG5 0.890495 EPSTI1 OAS3 ZBP1 0.890069 OAS1 OAS3 RIGE 0.89006 IFI44L RIG1 IFI44 0.88778 IFIT5 IFI44L IFI44 0.88776 RIG1 OAS3 XIAP 0.887549 IFI44 PARP9 CHMP5 0.887524 G1P2 OAS3 RIGE 0.887416 EPSTI1 CIG5 RIGE 0.887118 OAS2 CIG5 ZBP1 0.886902 OAS1 SP110 RIGE 0.88684 CIG5 PARP9 RIGE 0.886773 OAS2 OASL CIG5 0.886112 IFI44 SAMD9L CHMP5 0.885956 IFIT4 OASL RIGE 0.885918 IFIT5 RIG1 IFI44 0.885817 IRF7 CIG5 RIGE 0.885643 IRF7 OAS3 ZBP1 0.885583 OAS3 MX1 RIGE 0.885561 EPSTI1 OASL OAS3 0.883489 IRF7 SP110 ZBP1 0.883248 OAS3 XIAP ZBP1 0.883087 RIG1 PARP9 CHMP5 0.882158 IFIT4 OAS2 RIGE 0.881223 SP110 XIAP ZBP1 0.881076 OASL OAS3 PARP9 0.880696 OAS3 PARP9 ZBP1 0.880421 RIG1 IRF7 SP110 0.880086 EPSTI1 SP110 ZBP1 0.879636 RIG1 OASL ZBP1 0.879626 IRF7 PARP9 RIGE 0.87949 OASL OAS3 XIAP 0.879447 RIG1 SP110 XIAP 0.879006 OASL IRF7 OAS3 0.878692 RIG1 OAS3 PARP9 0.878538 OASL SP110 XIAP 0.876723 OASL PARP9 SP110 0.875724 RIG1 CIG5 OAS3 0.875511 CIG5 OAS3 ZBP1 0.875241 OASL IRF7 SP110 0.874351 PARP9 SP110 ZBP1 0.873999 OAS2 OAS3 PARP9 0.873713 CIG5 SP110 ZBP1 0.873581 IFIT5 IFI44L CHMP5 0.873435 EPSTI1 OASL SP110 0.872477 OAS2 EPSTI1 OAS3 0.872405 OAS2 PARP9 SP110 0.87155 EPSTI1 RIG1 SP110 0.871342 OASL CIG5 OAS3 0.870785 RIG1 CIG5 SP110 0.869263 EPSTI1 RIGE ZBP1 0.868804 IFIT4 OAS3 RIGE 0.868713 OASL CIG5 SP110 0.867945 IFI44L IFI44 CHMP5 0.867675 OAS2 IRF7 OAS3 0.867456 IFIT5 IFI44 CHMP5 0.867157 RIGE XIAP ZBP1 0.866861 IFI44L RIG1 CHMP5 0.864815 OAS2 IRF7 SP110 0.863904 IFIT5 RIG1 CHMP5 0.863765 OAS2 OAS3 XIAP 0.862892 OAS2 OASL ZBP1 0.862277 EPSTI1 OAS3 SP110 0.861466 IRF7 RIGE ZBP1 0.861372 OAS3 PARP9 SP110 0.861136 EPSTI1 RIG1 RIGE 0.860936 IFIT4 SP110 RIGE 0.860801 RIG1 RIGE XIAP 0.860302 OAS2 EPSTI1 SP110 0.860174 CIG5 RIGE ZBP1 0.859596 OAS2 SP110 XIAP 0.858564 EPSTI1 OASL RIGE 0.857914 OAS2 RIG1 OASL 0.857565 OASL RIGE XIAP 0.857553 OAS2 CIG5 OAS3 0.857493 IRF7 OAS3 SP110 0.857288 OAS3 SP110 XIAP 0.856743 RIG1 IFI44 CHMP5 0.855689 OAS2 RIG1 ZBP1 0.85545 RIG1 PARP9 SP110 0.855367 OAS2 CIG5 SP110 0.854157 OAS2 EPSTI1 RIGE 0.852592 PARP9 RIGE ZBP1 0.852095 OASL CIG5 RIGE 0.850683 RIG1 CIG5 RIGE 0.850622 OASL IRF7 RIGE 0.849649 CIG5 OAS3 SP110 0.849016 OAS2 RIGE XIAP 0.848472 OASL PARP9 RIGE 0.847797 RIG1 IRF7 RIGE 0.847049 OAS2 PARP9 RIGE 0.84672 OAS2 IRF7 RIGE 0.844908 OASL OAS3 ZBP1 0.843861 OAS2 CIG5 RIGE 0.84326 EPSTI1 OAS3 RIGE 0.843087 OASL SP110 ZBP1 0.840384 OAS3 RIGE XIAP 0.835809 RIG1 OAS3 ZBP1 0.835232 CIG5 OAS3 RIGE 0.830689 IRF7 OAS3 RIGE 0.830055 RIG1 OASL OAS3 0.829875 OAS3 PARP9 RIGE 0.829849 RIG1 PARP9 RIGE 0.827293 RIG1 SP110 ZBP1 0.827103 OAS2 OAS3 ZBP1 0.825923 OAS2 OASL OAS3 0.825647 EPSTI1 SP110 RIGE 0.824627 SP110 RIGE XIAP 0.823548 OASL RIGE ZBP1 0.821675 OAS2 SP110 ZBP1 0.821066 OAS2 OASL SP110 0.820454 CIG5 SP110 RIGE 0.819918 RIG1 OASL SP110 0.818533 OAS3 SP110 ZBP1 0.814438 IRF7 SP110 RIGE 0.814248 PARP9 SP110 RIGE 0.812561 OAS2 RIGE ZBP1 0.810229 OASL OAS3 SP110 0.809037 RIG1 RIGE ZBP1 0.806619 OAS2 OASL RIGE 0.804693 OAS2 RIG1 OAS3 0.803515 OAS3 RIGE ZBP1 0.79653 RIG1 OASL RIGE 0.79316 OASL OAS3 RIGE 0.789533 OAS2 OAS3 SP110 0.789077 OAS2 RIG1 SP110 0.78802 RIG1 OAS3 SP110 0.785883 SP110 RIGE ZBP1 0.781728 OAS2 RIG1 RIGE 0.777652 OAS2 OAS3 RIGE 0.7757 OASL SP110 RIGE 0.772656 RIG1 OAS3 RIGE 0.761256 OAS2 SP110 RIGE 0.75784 OAS3 SP110 RIGE 0.7529 RIG1 SP110 RIGE 0.725531 

1. A method comprising determining whether a subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein presence of said cell indicates that the subject has an autoimmune disorder.
 2. A method of predicting responsiveness of a subject to autoimmune disease therapy, said method comprising determining whether the subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein presence of said cell indicates that the subject would be responsive to the autoimmune disease therapy.
 3. A method for monitoring minimal residual disease in a subject treated for an autoimmune disease, said method comprising determining whether the subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of presence of minimal residual autoimmune disease.
 4. A method for detecting an autoimmune disease state in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of presence of an autoimmune disease state in the subject.
 5. A method for assessing predisposition of a subject to develop an autoimmune disorder, said method comprising determining whether the subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of a predisposition for the subject to develop the autoimmune disorder.
 6. A method for diagnosing an autoimmune disorder in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell indicates that the subject has said autoimmune disorder.
 7. The method of claim 1, wherein said at least 2 genes comprise (i) OAS3 and HERC5; or (ii) ESPTI1 and HERC5; or (iii) ESPTI1 and TYKI; or HERC5 and TYKI.
 8. The method of claim 1, wherein said at least 2 genes comprises a 3-gene combination as listed in Table 4B.
 9. The method of claim 8, wherein the 3-gene combination comprises (1) IFIT4, OAS1, and MX1; or (2) OASL, CHMP5, and ZBP1; or (3) IFI44L, OASL, and CIG5; or (4) IFI44L, CIG5, and ZBP1; or (5) EPSTI1, TYKI, and MX1; or (6) IFIT4, HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, and ZBP1; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OAS1, and IFIT1; or (11) EPSTI1, HERC5, and TYKI; or (12) IFI44L, EPSTI1, and OASL; or (13) IFI44L, EPSTI1, and OAS3; or (14) EPSTI1, TYKI, and IFIT1; or (15) G1P2, SAMD9L, and SP110.
 10. The method of claim 1, further comprising the use of a housekeeping gene.
 11. The method of claim 1, wherein the normal reference sample comprises a healthy cell or tissue.
 12. A composition comprising polynucleotides capable of specifically hybridizing to at least 2 of the genes listed in Table 1, 2, 3 and/or 4A or complements of said genes.
 13. The composition of claim 12, wherein the polynucleotides are provided as an array, a gene chip, or gene set.
 14. The composition of claim 12 comprising polynucleotides capable of specifically hybridizing to at least 3 genes listed in Table 1, 2, 3 and/or 4A or complements of said genes.
 15. The composition of claim 14, wherein said at least 3 genes comprises a 3-gene combination listed in Table 4B.
 16. The composition of claim 15, wherein the 3-gene combination comprises (1) IFIT4, OAS1, and MX1; or (2) OASL, CHMP5, and ZBP1; or (3) IFI44L, OASL, and CIG5; or (4) IFI44L, CIG5, and ZBP1; or (5) EPSTI1, TYKI, and MX1; or (6) IFIT4, HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, and ZBP1; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OAS1, and IFIT1; or (11) EPSTI1, HERC5, and TYKI; or (12) IFI44L, EPSTI1, and OASL; or (13) IFI44L, EPSTI1, and OAS3; or (14) EPSTI1, TYKI, and IFIT1; or (15) G1P2, SAMD9L, and SP110.
 17. The composition of claim 12, further comprising a housekeeping gene.
 18. A kit comprising the composition of claim 12, and instructions for using the composition to detect an autoimmune disorder by determining whether expression of the genes provided is at a level greater than the expression level of the respective genes in a normal reference sample.
 19. The kit of any of claim 18, wherein the normal reference sample comprises a healthy cell or tissue.
 20. A method of identifying a metric value correlated with presence and/or extent of an autoimmune disorder in a subject or sample, said method comprising: (a) estimating a group of probesets that is collectively associated with a pattern wherein expression of genes represented by the probesets is associated with a disease characteristic; (b) generating a weighting factor that weight probesets in accordance with a scale reflecting extent of match of each individual probeset to trend of the group of probesets, and calculating the correlation coefficient of each probeset's profile to the mean profile calculated; (c) determining a scaling factor, wherein the scaling factor is the value required to scale individual probesets to 1; (d) multiplying the scaling factor by the weighting factor to generate a composite factor; (e) multiplying a normal blood sample's signatures with the composite factor, and averaging the resulting values across both probesets and samples to generate an average value, and inverting the average value to yield a global scaling factor; (f) multiplying each weighting factor by the global scaling factor to obtain a vector of scalar values, and multiplying the scalar values by an expression signature from a sample of interest, and averaging the resulting values to yield a single metric that is indicative of degree of gene expression associated with Type I interferons in the sample.
 21. The method of claim 20, wherein in step (a), the group of probesets comprises probesets that include, or cluster around, the core most-tightly-correlated pair of probesets in subcluster associated with a disease characteristic.
 22. The method of the claim 20, wherein in step (b), the factor is generated by transforming expression data of the group of probesets into z-scores comprising mean scaling to 1, base-2 log transformation, then scaling to a standard deviation of the mean of
 1. 23. The method of claim 20, wherein in step (e), the global scaling factor is useful for transforming output of the average of probesets from a sample of interest into a metric, wherein the metric is 1 if the sample is from a normal, healthy subject.
 24. The method of claim 20, wherein the group of probesets comprises at least 2 of those listed in Table 1, 2, and/or
 3. 25. The method of claim 20, wherein the group of probesets comprises those listed in Table 1, 2, and/or
 3. 